Pyridazine compounds, compositions and methods

ABSTRACT

The invention relates to novel chemical compounds, compositions and methods of making and using the same. In particular, the invention provides pyridazine compounds and/or related heterocyclic derivatives, compositions comprising the same, and methods of making and using pyridazine compounds and/or related heterocyclic derivatives and compositions comprising the same, for modulation of cellular pathways (e.g., signal transduction pathways), for treatment or prevention of inflammatory diseases (e.g., Alzheimer&#39;s disease), for research, drug screening, and therapeutic applications.

RELATED APPLICATIONS

This application claims priority benefit from prior U.S. ProvisionalApplication Ser. No. 60/624,346 filed Nov. 2, 2004 and U.S. ProvisionalApplications Ser. No. 60/723,124, filed Oct. 3, 2005, and 60/723,090,filed Oct. 3, 2005.

This invention was funded, in part, under NIH grants P01AG21184 andR01NS47586, The US government may have certain rights in the invention.

FIELD OF INVENTION

The invention relates to novel chemical compounds, compositions andmethods of making and using the same. In particular, the inventionprovides pyridazine compounds and/or related heterocyclic derivatives,compositions comprising the same, and methods of using pyridazinecompounds and/or related heterocyclic derivatives and compositionscomprising the same, for modulation of cellular pathways (e.g., signaltransduction pathways), for treatment or prevention of inflammatorydiseases (e.g., Alzheimer's disease), for research, drug screening, andtherapeutic applications.

BACKGROUND OF INVENTION

The majority of inflammatory conditions and diseases result from adisruption in the homeostatic balance between beneficial and detrimentalresponses of the organism. For example, there may be a decrease in theproduction of trophic molecules that mediate cell survival and otherbeneficial cellular processes, or there may be an overproduction ofpro-inflammatory or other detrimental molecules that mediate toxiccellular responses. Disregulation of signal transduction pathwaysinvolving protein kinases are often involved in the generation orprogression of these diseases. For example, neuroinflammation is aprocess that results primarily from an abnormally high or chronicactivation of glia (microglia and astrocytes). This overactive state ofglia results in increased levels of inflammatory and oxidative stressmolecules, which can lead to neuron damage or death. Neuronaldamage/death can also induce glial activation, facilitating thepropagation of a localized, detrimental cycle of neuroinflammation [7].

The inflammation (e.g., neuroinflammation) cycle has been proposed as apotential therapeutic target in the development of new approaches totreat inflammatory disease (e.g., Alzheimer's disease), However, theefficacy and lexicological profile of compounds that focus only onclassical non-steroidal anti-inflammatory drug targets have beendisappointing to date, for example, most anti-inflammatory therapeuticsare palliative, providing minimal, short-lived, symptomatic relief withlimited effects on inflammatory disease (e.g., neuroinflammatorydiseases such as Alzheimer's disease) progression. Because the majorsocietal impact from inflammatory diseases (e.g., neuroinflammatorydiseases such as Alzheimer's disease) is expected to increase greatly incoming decades, there is an urgent need for anti-inflammatorytherapeutics that impact disease progression when administered soonafter diagnosis (e.g., diagnosis of cognitive decline), or in achemo-preventive paradigm as combinations of risk factors withprognostic value are identified. In either therapeutic paradigm, newdrugs must have a good therapeutic index, especially in regard topotential toxicology in the elderly.

Despite an overwhelming need, and the presence of well-defined moleculartargets, the current anti-inflammatory drug development pipeline islacking chemically diverse compounds that work within the relevanttherapeutic window and treatment paradigm needed for altering diseaseprogression. An area of comparative neglect that fits this therapeuticwindow is neuroinflammation [1]. Thus, development of new classes ofanti-inflammatory compounds that can modulate inflammatorydisease-relevant pathways are urgently needed.

SUMMARY OF INVENTION

The present invention relates to novel chemical compounds, compositionsand methods of making and using the same. In particular, the presentinvention provides pyridazine compounds and/or related heterocyclicderivatives, compositions comprising the same, and methods of usingpyridazine compounds and/or related heterocyclic derivatives, andcompositions comprising the same, for modulation of cellular pathways(e.g., signal transduction pathways), for treatment or prevention ofinflammatory diseases (e.g., Alzheimer's disease), for research, drugscreening, and therapeutic applications.

The invention provides a method for treating a disease disclosed herein,in particular an inflammatory disease in a subject comprisingadministering to the subject a pyridazinyl radical pendant with an arylor substituted aryl, in particular phenyl or substituted phenyl, aheteroaryl or substituted heteroaryl, in particular piperazinylsubstituted with pyrimidinyl, or pyridinyl.

In an aspect, the invention provides a method for treating a diseasedisclosed herein, in particular an inflammatory disease, in a subjectcomprising administering to the subject a compound of the Formula I,comprising Ia and Ib:

wherein R¹, R², and R³ are independently hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxamide; R⁷ is hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxaimde or R7 may be absent and there is adouble bond between N at position 1 and C at position 6; R⁴, R⁵, and R⁶are independently hydrogen, alkyl, alkoxy, halo, or nitro; or R¹ and R²,R¹ and R⁷, or R² and R³ may form a heteroaryl or heterocyclic ring; oran isomer or a pharmaceutically acceptable salt thereof.

In an embodiment, R¹ is a piperazinyl or substituted piperazinyl, inparticular a piperazinyl substituted with a pyrimidinyl of Formula Abelow.

Therefore, the invention also provides a method for treating a diseasedisclosed herein, in particular an inflammatory disease, in a subjectcomprising administering to the subject a compound of the Formula II:

wherein R¹⁰ and R¹¹ are independently hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceuticallyacceptable salt thereof

In an aspect, the invention provides a method for treating a diseasedisclosed herein, in particular an inflammatory disease, in a subjectcomprising administering to the subject a compound of the Formula III:

wherein R¹⁵ and R¹⁶ are independently hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention provides a method for treating adisease disclosed herein, in particular an inflammatory disease, in asubject comprising administering to the subject a compound of theFormula IV:

wherein R⁷⁰ is substituted or unsubstituted hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxamide, especially heterocyclic,heteroaryl, amino, and substituted amino and R⁷¹ is aryl or substitutedaryl; or an isomer or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides a method for treating adisease disclosed herein, in particular an inflammatory disease, in asubject comprising administering to the subject a compound of theFormula V:

wherein R⁵⁰, R⁵¹, and R⁵² are independently hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl,carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceuticallyacceptable salt thereof.

In an aspect, a method is provided for treating a disease disclosedherein in a subject comprising administering a compound of the FormulaI, II, III, IV, or V as defined herein, with the proviso that compoundsdepicted in Table 1 are excluded.

The invention relates to a method for treating diseases disclosed hereinin a subject comprising administering to the subject a therapeuticallyeffective amount of one or more compound of the Formula I, II, III, IV,or V, or a pharmaceutically acceptable salt thereof, or a compositioncomprising a compound of the Formula I, II, III, IV, or V and apharmaceutically acceptable carrier, excipient, or vehicle. In an aspectthe invention provides beneficial effects following treatment. Themethods of the invention can be used therapeutically or prophylacticallyin a subject susceptible to or having a genetic predisposition to adisease disclosed herein.

In another aspect of the invention, a method is provided for treating ina subject a disease involving or characterized by inflammation, inparticular neuroinflammation, comprising administering to the subject atherapeutically effective amount of a compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof. In afurther aspect, a method is provided for treating in a subject acondition involving inflammation, in particular neuroflammation,comprising administering to the subject a therapeutically effectiveamount of a composition comprising a compound of the Formula I, II, III,IV, or V and a pharmaceutically acceptable carrier, excipient, orvehicle.

In a further aspect, the invention provides a method involvingadministering to a subject a therapeutic compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of the Formula I, II, III, IV, or V,and a pharmaceutically acceptable carrier, excipient, or vehicle whichinhibit or reduce neuroflammation, activation of glia, proimflammatorycytokines, oxidative stress-related enzymes, acute phase proteins and/orcomponents of the complement cascade.

In another aspect, the invention provides a method for treating in asubject a disease associated with neuroinflammation that can bedecreased or inhibited with a compound disclosed herein comprisingadministering to the subject a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V, a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V, n particular the compounds depicted in theFigures and Tables, more particularly Table 2, 3, 4 or 5 and derivativesthereof and an isomer or pharmaceutically acceptable carrier, excipient,or vehicle.

Methods of the invention may be used to prevent or inhibit activation ofprotein kinases, in particular death associated protein kinase (DAPK);reduce or inhibit kinase activity, glial activation, neuronal celldamage, and/or neuronal cell death; inhibit cell signaling moleculeproduction (e.g., IL-1β and TNFα), amelioriate progression of a diseaseor obtain a less severe stage of a disease in a subject suffering fromsuch disease (e.g., neuroinflammatory disease, in particular aneurodegenerative disease, more particularly Alzheimer's disease); delaythe progression of a disease (e.g. neuroinflammatory disease, inparticular a neurodegenerative disease, more particularly Alzheimer'sdisease), increase survival of a subject suffering from a disease (e.g.neuroinflammatory disease, in particular a neurodegenerative disease,more particularly Alzheimer's disease; treat or prevent aneurodegenerative disease, in particular Alzheimer's disease; treat mildcognitive impairment (MCI); reverse or inhibit neuroinflammation,activation of signaling pathways involved in inflammation (e.g.,neuroinflammation), cell signaling molecule production, activation ofglia or glial activation pathways and responses, proinflammatorycytokines or chemokines (e.g., interleukin (IL) or tumor necrosis factor(TNF), oxidative stress-related responses such as nitric oxide synthaseproduction and nitric oxide accumulation, acute phase proteins,components of the complement cascade, protein kinase activity (e.g.,death associated protein kinase activity), neuronal cell damage, and/orneuronal cell death, after the onset of cognitive deficits andAlzheimer's disease neuropathology in a subject; improve memory of ahealthy subject or the memory of a subject with age impaired memory;improve memory, especially short-term memory and other mentaldysfunction associated, with the aging process; treat a mammal in needof improved memory, wherein the mammal has no diagnosed disease,disorder, infirmity or ailment known to impair or otherwise diminishmemory; and/or improve the lifespan of a subject suffering fromAlzheimer's disease.

The invention provides a method of preventing a disease disclosed hereinin a subject with a genetic predisposition to such disease byadministering an effective amount of a compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of the Formula I, II, III, IV, or Vand a pharmaceutically acceptable carrier, excipient, or vehicle.

The invention relates to compounds of the Formula I with the provisothat the compounds depicted in Table 1 are excluded.

The invention relates to compounds of the Formula II with the provisothat the compounds depicted in Table 1 are excluded.

The invention also relates to compounds of the Formula III with theproviso that compounds depicted in Table 1 are excluded.

The invention also relates to compounds of the Formula IV with theproviso that compounds depicted in Table 1 are excluded.

The invention also relates to compounds of the Formula V with theproviso that compounds depicted in Table 1 are excluded.

A compound of the Formula I, II, III, IV, or V may optionally comprise acarrier interacting with one or more radicals in the compound, forexample R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ in Formula I. A carrier may be apolymer, carbohydrate, or peptide, or combinations thereof, and it maybe optionally substituted, for example, with one or more alkyl, halo,hydroxyl, halo, or amino.

In accordance with aspects of the invention pyridazine compounds and/orrelated heterocyclic derivatives thereof (See, e.g., the Figures andTables herein, in particular Table 2, 3, 4 or 5 or derivatives thereof)are provided for use in research, drug screening, for modulation ofcellular pathways (e.g., signal transduction pathways), and fortreatment or prevention of inflammatory diseases (e.g., Alzheimer'sdisease). In some embodiments, the present invention provides newclasses of chemical compounds capable of modulating pro-inflammatory andoxidative stress related, cellular signaling pathways (e.g., inactivated glial cells). In some embodiments, one or more compounds ofthe Figures and Tables herein are used to modulate kinase activity aloneor in combination with other compounds or therapies. In someembodiments, compounds, and methods of using the compounds, provided bythe invention are those depicted in the Figures and Table 2, 3, 4,and/or 5 and derivatives thereof. In some embodiments, the inventionprovides MW01-3-5-183WH, MWO1-5-188WH, MWO1-2-065LKM, MWO1-2-184WH,MW01-2-189WH and MW01-2-151SRM and methods of synthesizing the same.

In some embodiments, the invention provides MW01-3-5-183WH,MWO1-5-188WH, MWO1-2-065LKM, MWO1-2-184WH, MW01-2-151SRM, MW01-2-189WH,MW01-1-01-L-D07, and/or related heterocyclic derivatives of thesecompounds and methods of making and using the same for modulatingcellular pathways (e.g., signal transduction pathways) for use inresearch, drug screening, and therapeutic applications.

In an aspect, the invention provides compositions for prevention and/ortreatment of a disease disclosed herein. Thus, the invention provides apharmaceutical composition comprising a compound of the Formula I, II,III, IV, or V, in particular a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V, more particularly acompound depicted in the Figures and Table 2, 3, 4, and/or 5 orderivatives thereof, for treating a disease. More particularly, theinvention provides a pharmaceutical composition in a form adapted toradministration to a subject to provide therapeutic effects, inparticular beneficial effects to treat a disease disclosed herein.

In another aspect, the composition is in a form such that administrationto a subject suffering from a disease results in a decrease or reversalof one or more of the following: inflammation (e.g. neuroinflammation),activation of signaling pathways involved in inflammation (e.g.,neuroinflammation), cell signaling molecule production, activation ofglia or glial activation pathways and responses, proinflammatorycytokines or chemokines (e.g., interleukin (IL) or tumor necrosis factor(TNF), oxidative stress-related responses such as nitric oxide synthaseproduction and nitric oxide accumulation, acute phase proteins,components of the complement cascade, protein kinase activity (e.g.,death associated protein kinase activity), cell damage (e.g., neuronalcell damage), and/or cell death (e.g., neuronal cell death). Acomposition of the invention can be in a form that results in one ormore of a decrease or reversal of one or more of the followinginflammation (e.g. neuroinflammation), activation of signaling pathwaysinvolved in inflammation (e.g., neuroinflammation), cell signalingmolecule production, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related, responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death) in a subject.

In an aspect, the invention features a composition comprising a compoundof the invention in a therapeutically effective amount for decreasing orreversing of one or more of the following: inflammation (e.g.neuroinflammation), activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death) in a subject. The composition can be in a pharmaceuticallyacceptable carrier, excipient, or vehicle.

Additionally the invention contemplates a method of preparing a stablepharmaceutical composition comprising one or more compound of theFormula I, II, III, IV, or V. After a composition is prepared, it can beplaced in an appropriate container and labeled for treatment of anindicated disease. For administration of a composition of the invention,such labeling would include amount, frequency, and method ofadministration.

In some aspects the invention provides methods to make commerciallyavailable pills, tablets, caplets, soft and hard gelatin capsules,lozenges, sachets, cachets, vegicaps, liquid drops, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium) suppositories, sterile injectable solutions, and/orsterile packaged powders, which contain a compound of the Formula I, II,III, IV, or V of the invention.

In an aspect, compounds and compositions of the invention may beadministered therapeutically or prophylactically to treat a diseasedisclosed herein. While not wishing to be bound by any particulartheory, the compounds and compositions may act to ameliorate the courseof a disease using without limitation one or more of the followingmechanisms: preventing, reducing and/or inhibiting inflammation (e.g.neuroinflammation), activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death).

The invention relates to the use of a composition comprising at leastone compound of the Formula I, II, III, IV, or V for the preparation ofa medicament for treating a disease disclosed herein. The inventionadditionally relates to uses of a pharmaceutical composition of theinvention in the preparation of medicaments for the prevention and/ortreatment of a disease disclosed herein. The medicament may be in a formsuitable for consumption by a subject, for example, a pill, tablet,caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap,liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (asa solid or in a liquid medium) suppository, sterile injectable solution,and/or sterile packaged powder.

The invention further relates to a kit comprising one or more compoundof the Formula I, II, III, IV, or V or a composition comprising acompound of the Formula I, II, III, IV, or V. In an aspect, theinvention provides a kit for preventing and/or treating, a diseasedisclosed herein comprising one or more compound of the Formula I, II,III, IV, or V, a container, and instructions for use. The composition ofa kit of the invention can further comprise a pharmaceuticallyacceptable carrier, excipient, or vehicle.

The compounds of the Formula I, II, III, IV, or V (in particular thecompounds depicted in Table 2, 3, 4 and/or 5 or derivatives thereof)provide a structural scaffold on which to base compositions fordecreasing or reversing one or more of the following: inflammation (e.g.neuroinflammation), activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death), wherein the compound comprise a structure of Formula I, II,III, IV, or V.

Thus, the invention also contemplates libraries or collections ofcompounds all of which are represented by a compound of the Formula I,II, III, IV, or V, in particular a compound depicted in Table 2, 3, 4,and/or 5 or derivatives thereof. In particular, the inventioncontemplates a combinatorial library comprising compounds for decreasingor reversing one or more of the following: inflammation (e.g.neuroinflammation), activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death), wherein the compound comprise a structure of Formula I, II,III, IV, or V.

These and other aspects, features, and advantages of the presentinvention should be apparent to those skilled in the art from thefollowing detailed description.

DESCRIPTION OF THE FIGURES

FIG. 1 depicts a synthetic scheme for synthesis of MWO1-3-183WH.

FIG. 2, parts (A) and (B), are graphs showing concentration dependentinhibition of proinflammatory cytokine production by MWO1-3-183WH inBV-2 cells

FIG. 3, parts (A) thru (H), show graphs and micrographs of activity ofMW01-5-188WH. (A) is a graph of IL-1β and (B) TNFα levels by the BV2microglial cell line, (C) Accumulation of the NO metabolite, nitrite,was not inhibited; Western blots of iNOS, COX-2 or apoE production inactivated glia in (D); iNOS, (E) COX-2 and (F) apoE from glia cultures.Micrographs of treatment with diluent and compound are shown in (G) and(H).

FIG. 4, parts (A) thru (H), shows graphs and micrographs of activity ofMW01-5-188WH after oral administration.

FIG. 5, parts (A) thru (C), shows graphs of results of oraladministration of MW01-5-188WH.

FIG. 6, parts (A) thru (D), shows graphs and immunoblots illustratingthe cell-based activity of MW01-2-151SRM in BV-2 microglial cells.

FIG. 7, parts (A) thru (G), shows graphs illustrating in vivo activityof MW01-2-151SRM in the Aβ infusion mouse model. Graphs are ofMW01-2-151SRM suppression of Aβ-induced neuroinflammation and synapticdamage and activity in the Y-maze. Hippocampal sections or extracts fromvehicle-infused mice (control). Aβ-infused mice injected with solvent,and Aβ-infused mice injected with MW01-2-151SRM were evaluated forneuroinflammation by measurement of the levels of the pro-inflammatorycytokines IL-1β (A), TNFα (B), and S100B (C), and the number ofGFAP-positive astrocytes, (D) and the presynaptic marker, synaptophysin,(E), and evaluated for synaptic damage by analysis of the levels of thepost-synaptic density protein 95 (PSD-95) (F), and Y-maze. Data are fromone of two independent experiments, and are the mean +SEM for 4-5 miceper experimental group.

FIG. 8 is a synthetic scheme for MW01-7-084WH.

FIG. 9 is a synthetic scheme for MW01-7-085WH.

FIG. 10 is a synthetic scheme for MW01-7-091WH.

FIG. 11 is a synthetic scheme for MW01-2-065LKM.

FIG. 12 is a synthetic scheme for MW01-2-069A-SRM.

FIG. 13 is a synthetic scheme for MW01-2-151 SRM.

FIG. 14 is a synthetic scheme for MW01-2-151SRM.

FIG. 15 is a synthetic scheme for MW01-2-151SRM.

FIG. 16 is a synthetic scheme for MW01-5-188WH.

FIG. 17 is a synthetic scheme for MW01-5-188WH.

FIG. 18 is a synthetic scheme for MW01-5-188 WH.

FIG. 19, parts (A) and (B), are synthetic schemes for MW01-6-189WH.

FIG. 20 is a synthetic scheme for MW01-7-029WH.

FIG. 21 is a synthetic scheme for MW01-7-027B-WH.

FIG. 22 is a synthetic scheme for MW01-3-065SRM.

FIG. 23 is a synthetic scheme for MW01-3-066SRM.

FIG. 24 is a synthetic scheme for MW01-7-133WH.

FIG. 25 is a synthetic scheme for MW01-7-107WH.

FIG. 26 is a synthetic scheme for MW01-7-057WH.

FIG. 27 is a synthetic scheme for MW01-2-163MAS.

FIG. 28 is a synthetic scheme for MW01-7-084WH.

FIG. 29, parts (A) thru (C), shows graphical data of the assays usedherein for MW01-2-056WH.

FIG. 30, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-2-056WH.

FIG. 31, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-7-057WH.

FIG. 32, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-7-057WH.

FIG. 33, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-2-065LKM.

FIG. 34, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-2-065LKM.

FIG. 35, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-2-069A-SRM.

FIG. 36, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-2-069A-SRM.

FIG. 37, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-7-085WH.

FIG. 38, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-7-085WH.

FIG. 39, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-7-091WH.

FIG. 40, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-7-091WH.

FIG. 41, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-7-107WH.

FIG. 42, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-7-107WH.

FIG. 43, parts (A) thru (C), shows graphical data of the assays usedherein and immunobiots for biological activity of MW01-7-127WH.

FIG. 44, parts (A) thru (E), shows graphical data of the assays usedherein for MW01-7-127WH.

FIG. 45, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-2-151SRM.

FIG. 46, parts (A) thru (H), shows graphical data of the assays usedherein for MW01-2-151SRM.

FIG. 47, parts (A) and (B), are graphs of response to MW01-2-151SRM, ina test for toxicity where DMSO in saline was the control, and QTcinterval measurement. QT intervals were obtained at baseline and at 15min, 30 min, 45 min, and 60 min after compound administration.

FIG. 48, parts (A) thru (F), are graphs of stability data using human(A,B) and rat (C,D) microsomes with MW01-2-151SRM in two differentamounts, for two time periods. E and F show human (E) and (F) ratmicrosomes with MW01-2-151SRM stability for different time periodscompared to minaprine.

FIG. 49, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-2-163MAS.

FIG. 50, parts (A) thru (C), shows graphical data of the assays usedherein and immunoblots for biological activity of MW01-6-189WH.

FIG. 51, parts (A) thru (D), shows graphical data of the assays usedherein for MW01-6-189WH.

DETAILED DESCRIPTION

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

Numerical ranges recited herein by endpoints include all numbers andfractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbersand fractions thereof are presumed to be modified by the term “about.”The term “about” means plus or minus 0.1 to 50%, 5-50%, or 10-40%,preferably 10-20%, more preferably 10% or 15%, of the number to whichreference is being made. Further, it is to be understood that “a,” “an,”and “the” include plural referents unless the content clearly dictatesotherwise. Thus, for example, reference to a composition comprising “acompound” includes a mixture of two or more compounds.

As used herein the terms “administering” and “administration” refer to aprocess by which a therapeutically effective amount of a compound orcomposition contemplated herein is delivered to a subject for preventionand/or treatment purposes. Compositions are administered in accordancewith good medical practices taking into account the subject's clinicalcondition, the site and method of administration, dosage, patient age,sex, body weight, and other factors known to physicians.

As used herein, the term “co-administration” refers to theadministration of at least two compounds or agent(s) (e.g., compound ofthe Formula I, II, III, IV, or V or pyridazines) or therapies to asubject. In some embodiments, the co-administration of two or moreagents/therapies is concurrent. In other embodiments, a firstagent/therapy is administered prior to a second agent/therapy. Those ofskill in the art understand that the Formulations and/or routes ofadministration of the various agents/therapies used may vary. Theappropriate dosage for co-administration can be readily determined byone skilled in the art. In some embodiments, when agents/therapies areco-administered, the respective agents/therapies are administered atlower dosages than appropriate for their administration alone. Thus,co-administration is especially desirable in embodiments where theco-administration of the agents/therapies lowers the requisite dosage ofa known potentially harmful (e.g., toxic) agent(s).

The term “treating” refers to reversing, alleviating, or inhibiting theprogress of a disease, or one or more symptoms of such disease, to whichsuch term applies. Depending on the condition of the subject, the termalso refers to preventing a disease, and includes preventing the onsetof a disease, or preventing the symptoms associated with a disease. Atreatment may be either performed in an acute or chronic way. The termalso refers to reducing the severity of a disease or symptoms associatedwith such disease prior to affliction with the disease. Such preventionor reduction of the severity of a disease prior to affliction refers toadministration of a compound or composition of the present invention toa subject that is not at the time of administration afflicted with thedisease. “Preventing” also refers to preventing the recurrence of adisease or of one or more symptoms associated with such disease.“Treatment” and “therapeutically,” refer to the act of treating, as“treating” is defined above.

The terms “subject”, “individual”, or “patient” are used interchangeablyherein and refer to an animal preferably a warm-blooded animal such as amammal. Mammal includes without limitation any members of the Mammalia.In general, the terms refer to a human. The terms also include domesticanimals bred for food or as pets, including equines, bovines, sheep,poultry, fish, porcines, canines, felines, and zoo animals, goats, apes(e.g. gorilla or chimpanzee), and rodents such as rats and mice.

In aspects of the invention, the terms refer to organisms to be treatedby the methods of the present invention. Such organisms preferablyinclude, but are not limited to, mammals (e.g., murines, simians,equines, bovines, porcines, canines, felines, and the like), and mostpreferably includes humans. In the context of particular aspects of theinvention, the term “subject” generally refers to an individual who willreceive or who has received treatment (e.g., administration of acompound of the Formula I, II, III, IV, or V or a pyridazinecompound(s), and optionally one or more other agents) for a conditioncharacterized by inflammation, the dysregulation of protein kinaseactivity, and/or dysregulation of apototic processes.

Typical subjects for treatment include persons afflicted with orsuspected of having or being pre-disposed to a disease disclosed herein,or persons susceptible to, suffering from or that have suffered adisease disclosed herein. A subject may or may not have a geneticpredisposition for a disease disclosed herein such as Alzheimer'sdisease. In particular aspects, a subject shows signs of cognitivedeficits and Alzheimer's disease neuropathology. In embodiments of theinvention the subjects are suspectible to, or suffer from Alzheimer'sdisease.

As utilized herein, the term “healthy subject” means a subject, inparticular a mammal, having no diagnosed disease, disorder, infirmity,or ailment, more particularly a disease, disorder, infirmity or ailmentknown to impair or otherwise diminish memory.

The term “diagnosed,” as used herein, refers to the recognition of adisease by its signs and symptoms (e.g., resistance to conventionaltherapies), or genetic analysis, pathological analysis, histologicalanalysis, and the like.

As used herein, the term “modulate” refers to the activity of a compound(e.g., a compound of the Formula I, II, III, IV, or V, or a pyridazinecompound) to affect (e.g., to promote or retard) an aspect of cellularfunction, including, but not limited to, cell growth, proliferation,apoptosis, and the like.

A “beneficial effect” refers to an effect of a compound of the inventionor composition thereof in certain aspects of the invention, includingfavorable pharmacological and/or therapeutic effects, and improvedbiological activity. In aspects of the invention, the beneficial effectsinclude without limitation prevention, reduction, reversal, orinhibition of one or more of the following: inflammation (e.g.neuroinflammation), activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity), celldamage (e.g., neuronal cell damage), and/or cell death (e.g., neuronalcell death). In some aspects, a beneficial effect is a favourablecharacteristic of a composition comprising a compound of the Formula I,II, III, IV, or V including without limitation enhanced stability, alonger half life, and/or enhanced uptake and transport across the bloodbrain barrier.

The beneficial effect can be a statistically significant effect in termsof statistical analysis of an effect of a compound of the formula I, II,III, IV, or V versus the effects without the compound or compound thatis not within the scope of the invention. Statistically significant” or“significantly different” effects or levels may represent levels thatare higher or lower than a standard. In aspects of the invention, thedifference may be 1.5, 2, 3, 4, 5, or 6 times higher or lower comparedwith the effect obtained without a compound of the Formula I, II, III,IV, or V.

The term “pharmaceutically acceptable carrier, excipient, or vehicle”refers to a medium which does not interfere with the effectiveness oractivity of an active ingredient and which is not toxic to the hosts towhich it is administered. A carrier, excipient, or vehicle includesdiluents, binders, adhesives, lubricants, disintegrates, bulking agents,wetting or emulsifying agents, pH buffering agents, and miscellaneousmaterials such as absorbants that may be needed in order to prepare aparticular composition. Examples of carriers etc. include but are notlimited to saline, buffered saline, dextrose, water, glycerol, ethanol,and combinations thereof. The use of such media and agents for an activesubstance is well known in the art.

The compounds of the Formula I, II, III, IV, or V disclosed herein alsoinclude “pharmaceutically acceptable salt(s)”. By pharmaceuticallyacceptable salts is meant those salts which are suitable for use incontact with the tissues of a subject or patient without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts aredescribed for example, in S. M. Berge, et al., J. PharmaceuticalSciences, 1977, 66:1. Examples of salts include MW01-1-01-L-D10,MW01-1-01-L-E02, MW01-1-01-L-E08, MW01-1-03-L-A05, MW01-1-16-L-D09, andMW01-1-17-L-G04.

A compound of the Formula I, II, III, IV, or V can contain one or moreasymmetric centers and may give rise to enantiomers, diasteriomers, andother stereoisomeric forms which may be defined in terms of absolutestereochemistry as (R)- or (S)-. Thus, compounds of the Formula I, II,III, IV, or V include all possible diasteriomers and enantiomers as wellas their racemic and optically pure forms. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. When a compound of the FormulaI, II, III, IV, or V contains centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand A geometric isomers. All tautomeric forms are also included withinthe scope of a compound of the Formula I, II, III, IV, or V.

A compound of the Formula I, II, III, IV, or V can exist in unsolvatedas well as solvated forms with pharmaceutically acceptable solvents suchas water, ethanol, and the like. The solvated forms may be consideredequivalent to the unsolvated forms for the purposes of the presentinvention.

“Therapeutically effective amount” relates to the amount or dose of anactive compound of the Formula I, II, III, IV, or V or compositioncomprising the same, that will lead to one or more desired effects, inparticular, one or more therapeutic effects, more particularlybeneficial effects. A therapeutically effective amount of a substancecan vary according to factors such as the disease state, age, sex, andweight of the subject, and the ability of the substance to elicit adesired response in the subject. A dosage regimen may be adjusted toprovide the optimum therapeutic response (e.g. sustained beneficialeffects). For example, several divided doses may be administered dailyor the dose may be proportionally reduced as indicated by the exigenciesof the therapeutic situation.

As used herein, the term “pure” in general means better than 95% pure,and “substantially pure” means a compound synthesized such that thecompound, as made or as available for consideration into a compositionor therapeutic dosage described herein, has only those impurities thatcan not readily nor reasonably be removed by conventional purificationprocesses.

The term “derivative” of a compound, as used herein, refers to achemically modified compound wherein the chemical modification takesplace either at a functional group of the compound or on the aromaticring. Non-limiting examples of derivatives of compounds of the FormulaI, II, III, IV, or V (e.g., pyridazine derivatives of the presentinvention) may include N-acetyl, N-methyl, N-hydroxy groups at any ofthe available nitrogens in the compound.

A “polymer” refers to molecules comprising two or more monomer subunitsthat may be identical repeating subunits or different repeatingsubunits. A monomer generally comprises a simple structure,low-molecular weight molecule containing carbon. Polymers may optionallybe substituted. Polymers that can be used in the present inventioninclude without limitation vinyl, acryl, styrene, carbohydrate derivedpolymers, polyethylene glycol (PEG), polyoxyethylene, polymethyleneglycol, poly-trimethylene glycols, polyvinylpyrrolidone,polyoxyethylene-polyoxypropylene block polymers, and copolymers, salts,and derivatives thereof. In aspects of the invention, the polymer ispoly(2-acrylamido-2-methyl-1-propanesulfonic acid);poly(2-acrylamido-2-methyl,-1-propanesulfonic acid-coacrylonitrile,poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-styrene),poly(vinylsulfonic acid); poly(sodium 4-styrenesulfonic acid); andsulfates and sulfonates derived therefrom; poly(acrylic acid),poly(methylacrylate), poly(methyl methacrylate), and poly(vinylalcohol).

A “carbohydrate” as used herein refers to a polyhydroxyaldehyde, orpolyhydroxyketone and derivatives thereof. The term includesmonosaccharides such as erythrose, arabinose, allose, altrose, glucose,mannose, threose, xylose, gulose, idose, galactose, talose, aldohexose,fructose, ketohexose, ribose, and aldopentose. The term also includescarbohydrates composed of monosaccharide units, including disaccharides,oligosaccharides, or polysaccharides. Examples of disaccharides aresucrose, lactose, and maltose. Oligosaccharides generally containbetween 3 and 9 monosaccharide units and polysaccharides contain greaterthan 10 monosaccharide units. A carbohydrate group may be substituted atone two, three or four positions, other than the position of linkage toa compound of the Formula I, II, III, IV, or V. For example, acarbohydrate may be substituted with one or more alkyl, amino, nitro,halo, thiol, carboxyl, or hydroxyl groups, which are optionallysubstituted. Illustrative substituted carbohydrates are glucosamine, orgalactosamine. In aspects of the invention, the carbohydrate is a sugar,in particular a hexose or pentose and may be an aldose or a ketose. Asugar may be a member of the D or L series and can include amino sugars,deoxy sugars, and their uronic acid derivatives. In embodiments of theinvention where the carbohydrate is a hexose, the hexose is glucose,galactose, or mannose, or substituted hexose sugar residues such as anamino sugar residue such as hexosamine, galactosamine, glucosamine, inparticular D-glucosamine (2-amino-2-doexy-D-glucose) or D-galactosamine(2-amino-2-deoxy-D-galactose). Illustrative pentose sugars includearabinose, fucose, and ribose.

A sugar residue may be linked to a compound of the Formula I, II, III,IV, or V from a 1,1 linkage, 1,2 linkage, 1,4 linkage, 1,5 linkage, or1,6 linkage. A linkage may be via an oxygen atom of a compound of theFormula I, II, III, IV, or V. An oxygen atom can be replaced one or moretimes by —CH₂— or —S— groups.

The term “carbohydrate” also includes glycoproteins such as lectins(e.g. concanavalin A, wheat germ agglutinin, peanutagglutinin,seromucoid, and orosomucoid) and glycolipids such as cerebroside andganglioside.

A “peptide” carrier for use in the practice of the present inventionincludes one, two, three, four, or five or more amino acids covalentlylinked through a peptide bond. A peptide can comprise one or morenaturally occurring amino acids, and analogs, derivatives, and congenersthereof. A peptide can be modified to increase its stability,bioavailability, solubility, etc. “Peptide analogue” and “peptidederivative” as used herein include molecules which mimic the chemicalstructure of a peptide and retain the functional properties of thepeptide. A carrier for use in the present invention can be an amino acidsuch as alanine, glycine, proline, methionine, serine, threonine,histidine, asparagine, alanyl-alanyl, prolyl-methionyl, orglycyl-glycyl. A carrier can be a polypeptide such as albumin,antitrypsin, macroglobulin, haptoglobin, caeruloplasm, transferring, α-or β-lipoprotein, β- or γ-globulin or fibrinogen.

Approaches to designing peptide analogues, derivatives and mimetics areknown in the art. For example, see Farmer, P. S. in Drug Design (E. J.Ariens, ed.) Academic Press, New York, 1980, vol 10, pp. 119-143; Ball.J. B. and Alewood, P. F. (1990) J Mol. Recognition 3:55; Morgan, B. A.and Gainor, J. A. (1989) Ann. Rep. Med. Chem. 24:243; and Freidinger, R.M. (1989) Trends Pharmacol Sci. 10:270. See also Sawyer, T. K. (1995)“Peptidomimetic Design and Chemical Approaches to Peptide Metabolism” inTaylor, M. D. and Amidon, G. L. (eds,) Peptide-Based Drug Design:Controlling Transport and Metabolism, Chapter 17; Smith, A. B. 3rd, etal. (1995) J. Am. Chem. Soc. 117:11113-11123: Smith, A. B. 3rd, et al.(1994) J. Am. Chem. Soc. 116:9947-9962; and Hirschman, R., et al. (1993)J. Am. Chem. Soc. 115:12550-12568.

A peptide can be attached to a compound of the Formula I, II, III, IV,or V through a functional group on the side chain of certain amino acids(e.g. serine) or other suitable functional groups. A carrier maycomprise four or more amino acids with groups attached to three or moreof the amino acids through functional groups on side chains. In anaspect, the carrier is one amino acid, in particular a sulfonatederivative of an amino acid, for example cysteic acid.

The term “alkyl”, either alone or within other terms such as “thioalkyl”and “arylalkyl”, means a monovalent, saturated hydrocarbon radical whichmay be a straight chain (i.e. linear) or a branched chain. An alkylradical for use in the present invention generally comprises from about1 to 20 carbon atoms, particularly from about 1 to 10, 1 to 8 or 1 to 7,more particularly about 1 to 6 carbon atoms, or 3 to 6. Illustrativealkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl,tert-pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, n-dodecyl,n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl,nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along withbranched variations thereof. In certain aspects of the invention analkyl radical is a C₁-C₆ lower alkyl comprising or selected from thegroup consisting of methyl, ethyl, n-propyl, n-butyl, pentyl, n-hexyl,isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl,tert-pentyl, and n-hexyl. An alkyl radical may be optionally substitutedwith substituents as defined herein at positions that do notsignificantly interfere with the preparation of compounds of the FormulaI, II, III, IV, or V and do not significantly reduce the efficacy of thecompounds. In certain aspects of the invention, an alkyl radical issubstituted with one to five substituents including halo, lower alkoxy,lower aliphatic, a substituted lower aliphatic, hydroxy, cyano, nitro,thio, amino, keto, aldehyde, ester, amide, substituted amino, carboxyl,sulfonyl, sulfinyl, sulfenyl, sulfate, sulfoxide, substituted carboxyl,halogenated lower alkyl (e.g. CF₃), halogenated lower alkoxy,hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, loweralkylcarbonylamino, cycloaliphatic, substituted cycloaliphatic, or aryl(e.g., phenylmethyl (i.e. benzyl)). Substituent on an alkyl group maythemselves be substituted.

As used herein in respect to certain aspects of the invention, the term“substituted aliphatic” refers to an alkyl or an alkane possessing lessthan 10 carbons where at least one of the aliphatic hydrogen atoms hasbeen replaced by a halogen, an amino, a hydroxy, a nitro, a thio, aketone, an aldehyde, an ester, an amide, a lower aliphatic, asubstituted lower aliphatic, or a ring (aryl, substituted aryl,cycloaliphatic, or substituted cycloaliphatic, etc.). Examples of suchgroups include, but are not limited to, 1-chloroethyl and the like.

As used herein in respect, to certain aspects of the invention, the term“lower-alkyl-substituted-amino” refers to any alkyl unit containing upto and including eight carbon atoms where one of the aliphatic hydrogenatoms is replaced by an amino group. Examples of such include, but arenot limited to, ethylamino and the like.

As used herein in respect to certain aspects of the invention, the term“lower-alkyl-substituted-halogen” refers to any alkyl chain containingup to and including eight carbon atoms where one of the aliphatichydrogen atoms is replaced by a halogen. Examples of such include, butare not limited to, clorethyl and the like.

As used herein, the term “acetylamino” shall mean any primary orsecondary amino that is acetylated. Examples of such include, but arenot limited to, acetamide and the like.

As used herein the term “alkenyl” refers to an unsaturated, acyclicbranched or straight-chain hydrocarbon radical comprising at least onedouble bond. An alkenyl radical may contain from about 2 to 10 carbonatoms, in particular from about 3 to 8 carbon atoms and moreparticularly about 3 to 6 carbon atoms. Suitable alkenyl radicalsinclude without limitation ethenyl, propenyl (e.g., prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), buten-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, hexen-1-yl,3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like. Analkenyl radical may be optionally substituted similar to alkyl.

As used herein, the term “alkynyl” refers to an unsaturated, branched orstraight-chain hydrocarbon radical comprising one or more triple bonds.An alkynyl radical may contain about 1 to 20, 1 to 15, or 2-10 carbonatoms, particularly about 3 to 8 carbon atoms and more particularlyabout 3 to 6 carbon atoms. Suitable alkynyl radicals include withoutlimitation ethynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl, butynylssuch as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, pentynyls such aspentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl,hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and3,3-dimethylbutyn-1-yl radicals and the like. An alkenyl may beoptionally substituted similar to alkyl. The term “cycloalkynyl” refersto cyclic alkynyl groups.

As used herein the term “alkylene” refers to a linear or branchedradical having from about 1 to 10 carbon atoms and having attachmentpoints for two or more covalent bonds. Examples of such radicals aremethylene, ethylene, propylene, butylene, pentylene, hexylene,ethylidene, methylelhylene, and isopropylidene. When an alkenyleneradical is present as a substituent on another radical it is typicallyconsidered to be a single substituent rather than a radical formed bytwo substituents.

As used herein the term “alkenylene” refers to a linear or branchedradical having from about 2 to 10 carbon atoms, at least one doublebond, and having attachment points for two or more covalent bonds.Examples of alkenylene radicals include 1,1-vinylidene (—CH₂═C—),1,2-vinylidene (—CH═CH—), and 1,4-butadienyl (—CH═CH—CH═CH—).

As used herein the term “halo” refers to a halogen such as fluorine,chlorine, bromine or iodine atoms.

As used herein the term “hydroxyl” or “hydroxy” refers to an —OH group.

As used herein the term “cyano” refers to a carbon radical having threeof four covalent bonds shared by a nitrogen atom, in particular —C≡N. Acyano group may be substituted with substituents described herein.

As used herein the term “alkoxy” refers to a linear or branchedoxy-containing radical having an alkyl portion of one to about tencarbon atoms, such as a methoxy radical, which may be substituted. Inaspects of the invention an alkoxy radical may comprise about 1-10, 1-8or 1-6 carbon atoms. In embodiments of the invention, an alkoxy radicalcomprises about 1-6 carbon atoms and includes a C₁-C₆ alkyl-O-radicalwherein C₁-C₆ alkyl has the meaning set out herein. Examples of alkoxyradicals include without limitation methoxy, ethoxy, propoxy, butoxy,isopropoxy and tert-butoxy alkyls. An “alkoxy” radical may optionally besubstituted with one or more substitutents disclosed herein includingalkyl atoms to provide “alkylalkoxy” radicals; halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals (e.g.fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropox) and “haloalkoxyalkyl” radicals (e.g. fluoromethoxymethyl,chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, andtrifluoroethoxymethyl).

As used herein the term “alkenyloxy” refers to linear or branchedoxy-containing radicals having an alkenyl portion of about 2 to 10 tencarbon atoms, such as an ethenyloxy or propenyloxy radical. Analkenyloxy radical may be a “lower alkenyloxy” radical having about 2 to6 carbon atoms. Examples of alkenyloxy radicals include withoutlimitation ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxyalkyls. An “alkenyloxy” radical may be substituted with one or moresubstitutents disclosed herein including halo atoms, such as fluoro,chloro or bromo, to provide “haloalkenyloxy” radicals (e.g.trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, andfluoropropenyloxy).

A “carbocylic” includes radicals derived from a saturated orunstaturated, substituted or unsubstituted 5 to 14 member organicnucleus whose ring forming atoms (other than hydrogen) are solelycarbon. Examples of carbocyclic radicals are cycloalkyl, cycloalkenyl,aryl, in particular phenyl, naphthyl, norbornanyl, bicycloheptadienyl,tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,phenylcyclohexyl, acenapththylenyl, anthracenyl, biphenyl, bibenzylyl,and related bibenzylyl homologs, octahydronaphthyl, tetrahydronaphthyl,octahydroquinolinyl, dimethoxytetrahydronaphthyl and the like.

As used herein, the term “cycloalkyl” refers to radicals having fromabout 3 to 15 carbon atoms and containing one, two, three, or four ringswherein such rings may be attached in a pendant manner or may be fused,in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, adamantyl, and the like. In certainaspects of the invention the cycloalkyl radicals are “lower cycloalkyl”radicals having from about 3 to 8 carbon atoms, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Insome aspects of the invention the term “cycloalkyl” embraces radicalswhere cycloalkyl radicals are fused with aryl radicals or heterocyclylradicals. A cycloalkyl radical may be optionally substituted with groupsas disclosed herein.

As used herein in respect to certain aspects of the invention, the term“cycloaliphatic” refers to a cycloalkane possessing less than 8 carbonsor a fused ring system consisting of no more than three fusedcycloaliphatic rings. Examples of such include, but are not limited to,decalin and the like.

As used herein in respect to certain aspects of the invention, the term“substituted cycloaliphatic” refers to a cycloalkane possessing lessthan 8 carbons or a fused ring system consisting of no more than threefused rings, and where at least one of the aliphatic hydrogen atoms hasbeen replaced by a halogen, a nitro, a thio, an amino, a hydroxy, aketone, an aldehyde, an ester, an amide, a lower aliphatic, asubstituted lower aliphatic, or a ring (aryl, substituted aryl,cycloaliphatic, or substituted, cycloaliphatic). Examples of suchinclude, but are not limited to, 1-chlorodecalyl and the like.

A used herein, the term “cycloalkenyl” refers to radicals comprisingabout 2 to 15 carbon atoms, one or more carbon-carbon double bonds, andone, two, three, or four rings wherein such rings may be attached in apendant manner or may be fused. In certain aspects of the invention thecycloalkenyl radicals are “lower cycloalkenyl” radicals having three toseven carbon atoms. Examples of cycloalkenyl radicals include withoutlimitation cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.A cycloalkenyl radical may be optionally substituted with groups asdisclosed, herein, in particular 1, 2, or 3 substituents which may bethe same or different.

As used herein the term “cycloalkoxy” refers to cycloalkyl radicalsattached to an oxy radical. Examples of cycloalkoxy radicals includecyclohexoxy and cyclopentoxy. A cycloalkoxy radical may be optionallysubstituted with groups as disclosed herein.

As used herein, the term “aryl”, alone or in combination, refers to acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendant manner or may be fused.The term “fused” means that a second ring is present (i.e, attached orformed) by having two adjacent atoms in common or shared with the firstring. Illustrative “aryl” radicals includes without limitation aromaticradicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl,benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl,biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, andanthracenyl. An aryl radical may be optionally substituted with groupsas disclosed herein, in particular hydroxyl, alkyl, carbonyl, carboxyl,thiol, amino, and/or halo, in particular a substituted aryl includeswithout limitation arylamine and arylalkyamine.

As used herein in respect to certain aspects of the invention, the term“substituted aryl” refers to an aromatic ring, or fused aromatic ringsystem consisting of no more than three fused rings at least one ofwhich is aromatic, and where at least one of the hydrogen atoms on aring carbon has been replaced by a halogen, an amino, a hydroxy, anitro, a thio, an alkyl, a ketone, an aldehyde, an ester, an amide, alower aliphatic, a substituted lower aliphatic, or a ring (aryl,substituted aryl, cycloaliphatic, or substituted cycloaliphatic).Examples of such include, but are not limited to, hydroxyphenyl,chlorophenyl and the like.

As used herein, the term “aryloxy” refers to aryl radicals, as definedabove, attached to an oxygen atom. Exemplary aryloxy groups includenapthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.

As used herein the term “arylalkoxy,” refers to an aryl group attachedto an alkoxy group. Representative examples of arylalkoxy include, butare not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and5-phenylpentyloxy.

As used herein, the term “aroyl” refers to aryl radicals, as definedabove, attached to a carbonyl radical as defined herein, includingwithout, limitation benzoyl and toluoyl. An aroyl radical may beoptionally substituted with groups as disclosed herein.

As used herein the term “heteroaryl” refers to fully unsaturatedheteroatom-containing ring-shaped aromatic radicals having at least oneheteroatom selected from carbon, nitrogen, sulfur and oxygen. Aheteroaryl radical may contain one, two or three rings and the rings maybe attached in a pendant manner or may be fused. Examples of“heteroaryl” radicals, include without limitation, an unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, tetrazolyl and the like; an unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, in particular,indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl,quinolizidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl,phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, carbazolyl,purinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolinyl,isoquinolinyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl and thelike; an unsaturated 3 to 6-membered heteromonocyclic group containingan oxygen atom, in particular, 2-furyl, 3-furyl, pyranyl, and the like:an unsaturated 5 to 6-membered heteromonocyclic group containing asulfur atom, in particular, thienyl, 2-thienyl, 3-thienyl, and the like;unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, in particular, furazanyl,benzofurazanyl, oxazolyl, isoxazolyl, and oxadiazolyl; an unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, in particular benzoxazolyl, benzoxadiazolyl and thelike; an unsaturated 5 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,isothiazolyl, thiadiazolyl and the like; an unsaturated condensedheterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogenatoms such as benzothiazolyl, benzothiadiazolyl and the like. The termalso includes radicals where heterocyclic radicals are fused with arylradicals, in particular bicyclic radicals such as benzofuranyl,benzothiophenyl, phthalazinyl, chromenyl, xanthenyl, and the like. Aheteroaryl radical may be optionally substituted with groups asdisclosed herein, for example with an alkyl, amino, halogen, etc., inparticular a heteroarylamine.

The term “heterocyclic” refers to saturated and partially saturatedheteroatom-containing ring-shaped radicals having at least oneheteroatom selected from carbon, nitrogen, sulfur and oxygen. Aheterocyclic radical may contain one, two or three rings wherein suchrings may be attached in a pendant manner or may be fused. Examplarysaturated heterocyclic radicals include without 1 initiation a saturated3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl]; asaturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl];and, a saturated 3 to 6-membered heteromonocyclic group containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl] etc.Examples of partially saturated heterocyclyl radicals include withoutlimitation dihydrothiophene, dihydropyranyl, dihydrofuranyl anddihydrothiazolyl. Illustrative heterocyclic radicals include withoutlimitation aziridinyl, azetidinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, azepinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, pyrazolinyl, 1,4-dithianyl,thiomorpholinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothiopyranyl, thioxanyl, indolinyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3H-indolyl,quinuclidinyl, quinolizinyl, and the like.

As used herein in respect to certain aspects of the invention, the term“heterocyclic” refers to a cycloalkane and/or an aryl ring system,possessing less than 8 carbons, or a fused ring system consisting of nomore than three fused rings, where at least one of the ring carbon atomsis replaced by oxygen, nitrogen or sulfur. Examples of such include, butare not limited to, morpholino and the like.

As used herein in respect to certain aspects of the invention, the term“substituted heterocyclic” refers to a cycloalkane and/or an aryl ringsystem, possessing less than 8 carbons, or a fused ring systemconsisting of no more than three fused rings, where at least one of thering carbon atoms is replaced by oxygen, nitrogen or sulfur, and whereat least one of the aliphatic hydrogen atoms has been replaced by ahalogen, hydroxy, a thio, nitro, an amino, a ketone, an aldehyde, anester, an amide, a lower aliphatic, a substituted lower aliphatic, or aring (aryl, substituted aryl, cycloaliphatic, or substitutedcycloaliphatic). Examples of such include, but are not limited to2-chloropyranyl.

The foregoing heteroaryl and heterocyclic groups may be C-attached orN-attached (where such is possible).

As used herein the term “sulfonyl”, used alone or linked to other termssuch as alkylsulfonyl or arylsulfonyl, refers to the divalent radicals—SO₂ ⁻. In aspects of the invention a sulfonyl group, the sulfonyl groupmay be attached to a substituted or unsubstituted hydroxyl, alkyl group,ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group,cycloalkenyl group, cycloalkynyl group, heterocyclic group,carbohydrate, peptide, or peptide derivative.

The term “sulfinyl”, used alone or linked to other terms such asalkylsulfinyl (i.e. —S(O)-alkyl) or arylsulfinyl, refers to the divalentradicals —S(O)—.

As used herein the term “amino”, alone or in combination, refers to aradical where a nitrogen atom (N) is bonded to three substituents beingany combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl,alkynyl, aryl, silyl, heterocyclic, or heteroaryl with the generalchemical formula —NR²¹R²² where R²¹ and R²² can be any combination ofhydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl,carbonyl carboxyl, amino, silyl, heteroaryl, or heterocyclic which mayor may not be substituted. Optionally one substituent on the nitrogenatom may be a hydroxyl group (—OH) to provide an amine known as ahydroxylamine. Illustrative examples of amino groups are amino (—NH₂),alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino,arylalkylamino, and lower alkylsilylamino, in particular methylamino,ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino,cyclopropylamino, benzylamino, allylamino, hydroxylamino,cyclohexylamino, piperidinyl, hydrazinyl, benzylamino,diphenylmethylamino, tritylamino, trimethylsilylamino, anddimethyl-tert-butylsilylamino, which may or may not be substituted.

As used herein the term “thiol” means —SH. A thiol may be substitutedwith a substituent disclosed herein, in particular alkyl(thioalkyl),aryl(thioaryl), alkoxy(thioalkoxy) or carboxyl

The term “sulfenyl” used alone or linked to other terms such asalkylsulfenyl, refers to the radical —SR²⁴ wherein R²⁴ is not hydrogen.In aspects of the invention R²⁴ is substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl aryl, silyl, silylalkyl, heterocyclic,heteroaryl, carbonyl, carbamoyl, alkoxy, or carboxyl.

As used herein, the term “thioalkyl”, alone or in combination, refers toa chemical functional group where a sulfur atom (S) is bonded to analkyl, which may be substituted. Examples of thioalkyl groups arethiomethyl, thioethyl, and thiopropyl. A thioalkyl may be substitutedwith a substituted or unsubstitute carboxyl, aryl, heterocylic,carbonyl, or heterocyclic.

A thiol may be substituted with a substituted or unsubstitutedheteroaryl or heterocyclic, in particular a substituted or unsubstitutedsaturated 3 to 6-membered heteromonocylic group containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, andpiperazinyl] or a saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl; sydnonyl], especially a substituted morpholinyl orpiperidinyl.

As used herein the term, “thioaryl”, alone or in combination, refers toa chemical functional group where a sulfur atom (S) is bonded to an arylgroup with the general chemical formula —SR²⁵ where R²⁵ is aryl whichmay be substituted. Illustrative examples of thioaryl groups andsubstituted thioaryl groups are thiophenyl, chlorothiophenyl,para-chlorothiophenyl, thiobenzyl, 4-methoxy-thiophenyl,4-nitro-thiophenyl, and para-nitrothiobenzyl.

As used herein the term “thioalkoxy”, alone or in combination, refers toa chemical functional group where a sulfur atom (S) is bonded to analkoxy group with the general chemical formula —SR³⁰ where R³⁰ is analkoxy group which may be substituted. A “thioalkoxy group” may have 1-6carbon atoms i.e. a —S—(O)—C₁-C₆ alkyl group wherein C₁-C₆ alkyl havethe meaning as defined above. Illustrative examples of a straight orbranched thioalkoxy group or radical having from 1 to 6 carbon atoms,also known as a C₁-C₆ thioalkoxy, include thiomethoxy and thioethoxy.

As used herein, the term “carbonyl” refers to a carbon radical havingtwo of the four covalent bonds shared with an oxygen atom.

As used herein, the term “carboxyl”, alone or in combination, refers to—C(O)OR¹⁴— or —C(═O)OR¹⁴ wherein R¹⁴ is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl,thioalkyl, thioaryl, thioalkoxy, a heteroaryl, or a heterocyclic, whichmay optionally be substituted. Examples of carboxyl groups aremethoxycarbonyl, butoxycarbonyl, tert.alkoxycarbonyl such astert.butoxycarbonyl, arylmethyoxycarbonyl having one or two arylradicals including without limitation phenyl optionally substituted byfor example lower alkyl, lower alkoxy, hydroxyl, halo, and/or nitro,such as benzyloxycarbonyl, methoxybenxyloxycarbonyl,diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl,2-iodoethoxycarbonyltert.butylcarbonyl, 4-nitrobenzyloxycarbonyl,diphenylmethoxy-carbonyl, benzhydroxycarbonyl,di-(4-methoxyphenyl-methoxycarbonyl, 2-bromoethoxycarbonyl,2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or2-triphenylsilylethoxycarbonyl. Additional carboxyl groups in esterifiedform are silyloxycarbonyl groups including organic silyloxycarbonyl. Inaspects of the invention, the carboxyl group may be an alkoxy carbonyl,in particular methoxy carbonyl, ethoxy carbonyl, isopropoxy carbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, or heptyloxy carbonyl, especiallymethoxy carbonyl or ethoxy carbonyl.

As used herein, the term “carbamoyl”, alone or in combination, refers toamino, monoalkylamino, dialkylamino, monocycloalkylamino,alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one oftwo unshared bonds in a carbonyl group.

As used herein, the term “carboxamide” refers to the group —CONH—.

As used herein, the term “nitro” means —NO₂—.

As used herein, the term “acyl”, alone or in combination, means acarbonyl or thiocarbonyl group bonded to a radical selected from, forexample, optionally substituted, hydrido, alkyl (e.g. haloalkyl),alkenyl, alkynyl, alkoxy (“acyloxy” including acetyloxy, butyryloxy,iso-valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, andsubstituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo,heterocyclyl, heteroaryl, sulfinyl (e.g. alkylsulfinylalkyl), sulfonyl(e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl,thioaryl, amino (e.g alkylamino or dialkylamino), and aralkoxy.Illustrative examples of “acyl” radicals are formyl, acetyl,2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl,malonyl, nicotinyl, and the like.

As used herein, “ureido” refers to the group “—NHCONH—”. A ureidoradical includes an alkylureido comprising a ureido substituted with analkyl, in particular a lower alkyl attached to the terminal nitrogen ofthe ureido group. Examples of an alkylureido include without limitationN′-methylureido, N′-ethylureido, N′-n-propylureido, N′-i-propylureidoand the like. A ureido radical also includes a N′,N′-dialkylureido groupcontaining a radical —NHCON where the terminal nitrogen is attached totwo optionally substituted radicals including alkyl, aryl, heterocylic,and heteroaryl.

The terms used herein for radicals including “alkyl”, “alkoxy”,“alkenyl”, “alkynyl”, “hydroxyl” etc. refer to both unsubstituted andsubstituted radicals. The term “substituted,” as used herein, means thatany one or more moiety on a designated atom (e.g., hydrogen) is replacedwith a selection from a group disclosed herein, provided that thedesignated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or radicals are permissible only if such combinations result instable compounds. “Stable compound” refers to a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

A radical in a compound of the Formula I, II, III, IV, or V may besubstituted with one or more substituents apparent to a person skilledin the art including without limitation alkyl, alkoxy, alkenyl, alkynyl,alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene,haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl,alkylaryl, haloalkoxy, haloalkenyloxy, heterocyclic, heteroaryl,sulfonyl, alkylsulfonyl, sulfinyl, sulfonyl, sulfenyl, alkylsulfinyl,aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkoxy,cycloalkenyloxy, amino, oxy, halo, azido, thio, ═O, ═S, cyano, hydroxyl,phosphonato, phosphinato, thioalkyl, alkylamino, arylamino,arylsulfonyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,heteroarylsulfinyl, heteroarylsulfony, heteroarylamino, heteroaryloxy,heteroaryloxylalkyl, arylacetamidoyl, aryloxy, aroyl, aralkanoyl,aralkoxy, aryloxyalkyl, haloaryloxyalkyl, heteroaroyl, heteroaralkanoyl,heteroaralkoxy, heteroaralkoxyalkyl, thioaryl, arylthioalkyl,alkoxyalkyl, and acyl groups. These substitutents may themselves besubstituted.

A chemical substituent is “pendant” from a radical if it is bound to anatom of the radical. In this context, the substituent can be pendingfrom a carbon atom of a radical, a carbon atom connected to a carbonatom of the radical by a chain extender, or a heteroatom of the radical.

A “disease” that can be treated and/or prevented using a compound,composition, or method of the invention includes a condition associatedwith or requiring modulation of one or more of inflammation (e.g.neuroinflammation), signaling pathways involved in inflammation (e.g.,neuroinflammation), cell signaling molecule production, activation ofglia or glial activation pathways and responses, proinflammatorycytokines or chemokines (e.g., interleukin (IL) or tumor necrosis factor(TNF), oxidative stress-related responses such as nitric oxide synthaseproduction and nitric oxide accumulation, acute phase proteins,components of the complement cascade, protein kinase activity (e.g.,death associated protein kinase (DAPK) activity), cell damage (e.g.,neuronal cell damage), and cell death, (e.g., neuronal cell death). Inparticular a disease is a dementing disorder, a neurodegenerativedisorder, a CNS demyelinating disorder, an autoimmune disorder, or aperipheral inflammatory disease.

A disease may be characterized by an inflammatory process due to thepresence of macrophages activated by an amyloidogenic protein orpeptide. Thus, a method of the invention may involve inhibitingmacrophage activation and/or inhibiting an inflammatory process. Amethod may comprise decreasing, slowing, ameliorating, or reversing thecourse or degree of macrophage invasion or inflammation in a patient.

Examples of diseases that can be treated and/or prevented using thecompounds, compositions and methods of the invention include Alzheimer'sdisease and related disorders, presenile and senile forms; amyloidangiopathy; mild cognitive impairment; Alzheimer's disease-relateddementia (e.g., vascular dementia or Alzheimer dementia); AIDS relateddementia, tauopathies (e.g., argyrophilic grain dementia, corticobasaldegeneration, dementia pugilistica, diffuse neurofibrillary tangles withcalcification, frontotemporal dementia with parkinsonism, Prion-relateddisease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pickdisease type C, non-Guamanian Motor Neuron disease with neurofibrillarytangles, Pick's disease, postencephalitic parkinsonism, cerebral amyloidangiopathy, progressive subcortical gliosis, progressive supranuclearpalsy, subacute sclerosing panencephalitis, and tangle only dementia),alpha-synucleinopathy (e.g., dementia with Lewy bodies, multiple systematrophy with glial cytoplasmic inclusions), multiple system atrophies,Shy-Drager syndrome, spinocerebellar ataxia (e.g., DRPLA orMachado-Joseph Disease); striatonigral degeneration,olivopontocerebellar atrophy, neurodegeneration with brain ironaccumulation type I, olfactory dysfunction, and amyotrophic lateralsclerosis); Parkinson's disease (e.g., familial or non-familial);Amyotrophic Lateral Sclerosis; Spastic paraplegia (e.g., associated withdefective function of chaperones and/or triple A proteins); Huntington'sDisease, spinocerebellar ataxia, Freidrich's Ataxia; cerebrovasculardiseases including stroke, hypoxia, ischemia, infarction, intracerebralhemorrhage: traumatic brain injury; Down's syndrome; head trauma withpost-traumatic accumulation of amyloid beta peptide; Familial BritishDementia; Familial Danish Dementia; Presenile Dementia with SpasticAtaxia; Cerebral Amyloid Angiopathy, British Type; Presenile DementiaWith Spastic Ataxia Cerebral Amyloid Angiopathy, Danish Type; Familialencephalopathy with neuroserpin inclusion bodies (FENIB); AmyloidPolyneuropathy (e.g., senile amyloid polyneuropathy or systemicAmyloidosis); Inclusion Body myositis due to amyloid beta peptide;Familial and Finnish Type Amyloidosis; Systemic amyloidosis associatedwith multiple myeloma; Familial Mediterranean Fever; multiple sclerosis,optic neuritis; Guillain-Barre Syndrome; chronic inflammatorydemyelinating polyneuropathy; chronic infections and inflammations;acute disseminated encephalomyelitis (ADEM); autoimmune inner eardisease (AIED); diabetes; myocardial ischemia and other cardiovasculardisorders; pancreatitis; gout; inflammatory bowel disease; ulcerativecolitis, Crohn's disease, rheumatoid arthritis, osteoarthritis:artheriosclerosis, inflammatory aortic aneurysm; asthma; adultrespiratory distress syndrome; restenosis; ischemia/reperfusion injury;glomerulonephritis; sacoidosis cancer: restenosis; rheumatic fever;systemic lupus erythematosus; Reiter's syndrome; psoriatic arthritis;ankylosing spondylitis; coxarthritis; pelvic inflammatory disease:osteomyelitis; adhesive capsulitis; oligoarthritis; periarthritis;polyarthritis; psoriasis: Still's disease; synovitis; inflammatorydermatosis; and, wound healing.

In aspects of the invention, a compound, composition, or methoddisclosed herein may be utilized to prevent and/or treat a diseaseinvolving neuroinflammation (i.e., neuroinflammatory disease).Neuroinflammation is a characteristic feature of disease pathology andprogression in a diverse array of neurodegenerative disorders that areincreasing in their societal impact (for a recent review, see, e.g.,Prusiner, S. B. (2001) New Engl. J. Med. 344, 1516-1526). Theseneuroinflammation-related disorders include Alzheimer's disease (AD),amyotrophic lateral sclerosis, autoimmune disorders, priori diseases,stroke and traumatic brain injury. Neuroinflammation is brought about byglial cell (e.g., astrocytes and microglia) activation, which normallyserves a beneficial role as part of an organism's homeostatic responseto injury or developmental change. However, disregulation of thisprocess through chronic or excessive activation of glia contributes tothe disease process through the increased production of proinflammatorycytokines and chemokines, oxidative stress-related enzymes, acute phaseproteins, and various components of the complement cascades. (See, e.g.,Akiyama et al., (2000) Neurobiol. Aging 21, 383-421). The direct linkageof glial activation to pathology that is a hallmark of diseaseunderscores the importance of understanding the signal transductionpathways that mediate these critical glial cellular responses and thediscovery of cell permeable ligands that can modulate these diseaserelevant pathways.

For Alzheimer's disease (AD) in particular, the deposition of β-amyloid(Aβ) and neurofibrillary tangles are associated with glial activation,neuronal loss and cognitive decline. On a molecular level, Alzheimer'sdisease is characterized by; increased expression of nitric oxidesynthase (NOS) in glial cells surrounding amyloid plaques;neuropathological evidence of peroxynitrite-mediated neuronal damage;and nitric oxide (NO) overproduction involved in Aβ-induced braindysfunction. NOSH (iNOS) is induced as part of the glial activationresponse and is an oxidative stress-related enzyme that generates NO.When NO is present in high levels along with superoxide, the highlyreactive NO-derived molecule peroxynitrite is generated, leading toneuronal cell death. The pro-inflammatory cytokine IL-1β is alsooverexpressed in activated glia in AD brain and polymorphisms in IL-1βgenes are associated with an increased risk of early onset sporadic AD(See, e.g., Du et al, (2000) Neurology 55, 480-483). IL-1β can alsoinfluence amyloid plaque development and is involved in additional glialinflammatory and neuronal dysfunction responses (See, e.g., Griffin, etal., (1998) Brain Pathol. 8, 65-72; and Sheng, et al, (1996) Neurobiol,Aging 17, 761-766). Therefore, because glial activation and specificglial products are associated with neurodegenerative disorders (e.g.,Alzheimer's disease), the compounds and compositions disclosed hereinthat are capable of modulating cell signaling pathways (e.g., glialactivation pathways) will have particular application in the treatmentand prevention of inflammatory disease.

In aspects of the invention, a compound, composition, or methoddisclosed herein may be utilized to prevent and/or treat a diseaseinvolving disregulation of protein kinase signaling. Disregulation ofprotein kinase signaling often accompanies disregulation of cellsignaling pathways (e.g., glial cell activation pathways). Proteinkinases are a large family of proteins that play a central role inregulating a number of cellular functions including cell growth,differentiation and death. There are thought to be more than 500 proteinkinases and 130 protein phosphatases exerting tight control on proteinphosphorylation. Each protein kinase transfers the γ-phosphate of ATP toa specific residue(s) of a protein substrate. Protein kinases can befurther categorized as tyrosine, serine/threonine or dual specific basedon acceptor residue. Examples of serine/threonine kinases include MAPkinase, MAPK kinase (MEK), Akt/PKB, Jun kinase (INK), CDKs, proteinkinase A (PRA), protein kinase C (PKC), and calmodulin (CaM)-dependentkinases (CaMKs). Disregulated protein kinase activity (e.g., hyper- orhypo-active) leads to abnormal protein phosphorylation, underlying agreat number of diseases including diabetes, rheumatoid arthritis,inflammation, hypertension, and proliferative diseases such as cancer.Therefore, because aberrant kinase activity is associated withinflammatory disease (e.g., neurodegenerative disorders like Alzheimer'sdisease), the compounds and compositions that are disclosed herein thatare capable of modulating kinases involved in cell signaling pathwayswill have particular application for treatment and prevention ofinflammatory disease.

Compounds

The invention provides an isolated and pure, in particular,substantially pure, compound of the Formula I wherein R¹, R², and R³ areindependently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene,alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy,arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl,sulfinyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy,thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl,silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, or carboxamide; or R⁷is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene,alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy,aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl,sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl,nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O,═S, carboxyl, carbonyl, carbamoyl, or carboxamide: R⁴, R⁵, and R⁶ areindependently hydrogen, alkyl, alkoxy, halo, or nitro or R⁷ may beabsent with a double bond between N at position 1 and C at position 6;or R¹ and R², R¹ and R⁷, or R² and R³ may form a heteroaryl orheterocyclic ring; or an isomer or a pharmaceutically acceptable saltthereof.

In some aspects, one or more of the following compounds do not fallwithin the scope of the present invention:

In some aspects, one or more of the following compounds do not fallwithin the scope of the present invention:

-   a) a compound wherein when R² is ═O, R³ is —COOCH₃, CH═CHCOOCH₃,    —CH═CHC(═O)-phenyl, —CH═CH(C(═O)OCH₃)₂, —S-phenyl,    —CH—═CH(COCH₃)(COOCH₃), CH═CH(COOCH₂CH₃)₂, -phenyl-COOCH₃,    —CH—CHCO-phenyl, —CH₂CH(Cl)(CH₂OH), -methylphenyl, R⁷ is hydrogen or    —CH₂OCH₃, and R¹, R², R⁴, R⁵ and R⁶ are hydrogen;-   b) a compound wherein when R¹ is ═O, R² is cyano, R³ is —C(═O)OCH₃,    and R₃, R⁴, R⁵, and R⁶ are hydrogen;-   c) a compound wherein when R¹ is ═O, R² is -methylthiophene or    benzyl, R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen;-   d) a compound wherein when R¹ is ═O, R² is methyl, R⁵ is hydrogen,    hydroxyl, chloro, or bromo, R⁷ is hydrogen or ethylmorpholinyl, and    R³, R⁴, and R⁶ are hydrogen;-   e) a compound wherein when R² is methyl, R⁵ is chloro, bromo, or    hydrogen, R⁷ is hydrogen or —CH₂CH₂-morpholinyl, and R¹, R³, R⁴, and    R⁶ are hydrogen;-   f) a compound wherein when R¹ is piperazinyl, piperazinyl    substituted with pyridinyl, phenyl, or methyl, R² is hydrogen or    methyl, and R³, R⁴, R⁵, and R⁶ are hydrogen;-   g) a compound wherein when R¹ is chloro or bromo, R² is C₁-C₃ alkyl,    phenyl, amino, benzyl, morpholinyl, chloro, —C(═O)NH₂, —NH₂, C₁-C₃    alkylphenyl, —CH(CH₃)₂, —CH₂CH(CH₃)₂, -benzylchloro, and R³, R⁴, R⁵,    and R⁶ are hydrogen;-   h) a compound wherein when R¹ is chloro or bromo, R³ is hydroxyl,    chloro, bromo, C₁-C₃ alkyl, phenyl, or —N(CH₃)₂, and R³, R⁴, R⁵ and    R⁶ are hydrogen;-   i) a compound wherein when R¹ is chloro, R² is methyl, R⁵ is    hydroxyl, and R³, R⁴, and R⁶ are hydrogen;-   j) a compound wherein when R¹ is chloro, R², R³, R⁴, R⁵ and R⁶ are    hydrogen;-   k) a compound wherein when R¹ is hydroxyl, R² is C₁-C₄ alkyl, and    R³, R⁴, R⁵ and R⁶ are hydrogen:-   l) a compound wherein, when R¹ is —C₁-C₄ alkoxy, or C₁-C₄ alkoxy    substituted with —N(CH₃)₂, morpholinyl, or piperidinyl substituted    with benzyl, R² is hydrogen or methyl, R³, R⁴, R⁵ and R⁶ are    hydrogen, R⁷ is absent, hydrogen, or methyl;-   m) a compound wherein when R¹ is —SH, —SCH₃, or —SCH₂C(═O)CH₃, R² is    hydrogen or methyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   n) a compound wherein when R¹ is ═S, R² is hydrogen or methyl, R⁷ is    methyl or benzyl, and R³, R⁴, and R⁶ are hydrogen;-   o) a compound wherein when R¹ is ═S, R² is methyl and R⁵ is chloro    or R⁷ is methyl, and R³, R⁴, and R⁶ are hydrogen;-   p) a compound wherein when R¹ is hydroxyl, R² is hydrogen, methyl,    or butyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   q) a compound wherein when R¹ is methoxy, R², R³, R⁴, R⁵ and R⁶ are    hydrogen;-   r) a compound wherein when R¹ is C₁-C₂ alkoxy or C₁-C₄ alkoxy    substituted with morpholinyl, —N(CH₃)₂, or piperidinyl substituted    with benzyl, R² is methyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   s) a compound wherein R², R³, R⁴, R⁵ and R⁶ are hydrogen;-   t) a compound wherein R¹ is cyano or cyano substituted with    —C(OCH₂CH₃)₂, —CH(OH)(CH₃), —Si(CH₂CH₃)₂, cyclohexol,    —CH₂O-trimethyldiphenylsilyl or cyclohexyl substituted with    hydroxyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   u) a compound wherein R¹ is cyano substituted with —CH(OH)(CH₃)₂,    —Si(CH₂CH₃)₂, morpholinyl, trimethyldiphenylsilyl, or —CH(OCH₂CH₃)₂,    R² is methyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   v) a compound wherein R⁷ is oxy, and R² is hydrogen or methyl, and    R³, R⁴, R⁵ and R⁶ are hydrogen;-   w) a compound wherein R¹ is methyl, and R², R³, R⁴, R⁵ and R⁶ are    hydrogen;-   x) a compound wherein R² is methyl, and R¹, R³, R⁴, R⁵ and R⁶ are    hydrogen;-   y) a compound wherein R¹ is methoxycarbonyl, R³ is hydrogen, and R²,    R⁴, R⁵ and R⁶ are hydrogen;-   z) a compound wherein R¹ is —NH₂, R² is methyl, chlorophenyl,    methoxyphenyl, ethylphenyl, ethylmethoxyphenyl, propylphenyl, or    —CH(CH₃)₂, R⁴, R⁵ and R⁶ are hydrogen, and R⁷ is absent or    —CH₂CH₂CH₂COOH;-   aa) a compound wherein R¹ is ═OR⁸⁰ wherein R⁸⁰ is ethylmorpholinyl    or —CH₂CH₂N(CH₃)₂ and R², R³, R⁴, R⁵ and R⁶ are hydrogen;-   bb) a compound wherein R¹ is —NH₂, R³ is —NH₂, and R³, R⁴, R⁵ and R⁶    are hydrogen;-   cc) a compound wherein R¹ is —NH₂, R⁵ and R⁶ are methoxy, and R³ and    R⁴ are hydrogen;-   dd) a compound wherein R¹ is —NH₂, R⁵ is methyl and R⁴, R⁵ and R⁶    are hydrogen;-   ee) a compound wherein R¹ is —NH₂, R⁵ is chloro, and R³, R⁴and R⁶    are hydrogen;-   ff) a compound wherein R¹ is —NH-chlorophenyl, and R² and R³ form a    phenyl group, and R⁴, R⁵ and R⁶ are hydrogen;-   gg) a compound wherein R¹ is —NH₂, R⁴ and R⁵ is methoxy, and R², R³    and R⁶ are hydrogen;-   hh) a compound wherein R¹ is —NH₂, R² is ethylmethoxyphenyl, R⁷ is    carboxyethyl or carboxypropyl, and R³, R⁴ and R⁶ are hydrogen;-   ii) a compound wherein R¹ is —NHR²² wherein R²² is ethylmorpholinyl,    ethylmorpholinyl substituted with ═O, —CH₂CH₂OCH₃,    —CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂OH, or    —CH₂CH₂OCH₃, R² is hydrogen, methyl ethyl, —CHO, —CH₂OH, —COOH,    chloro, —CH₂CH₂NH₂, —NO₂, —C═N, —C(═O)OCH₂CH₃, or —C(═O)NH₂, and R³,    R⁴, R⁵ and R⁶ are hydrogen;-   jj) a compound wherein R¹ is —NHR²² wherein R²² is ethanol,    methylpiperidinylbenzyl, ethylpiperidinyl, ethylpiperldinylbenzyl,    or butylpiperidinylbenzyl, R² is hydrogen, methyl, or —C(CH₃)₂, and    R³, R⁴, R⁵ and R⁶ are hydrogen;-   kk) a compound, wherein R¹ is —NHR²² wherein R²² is hydrogen, and    R³, R⁴, R⁵ and R⁶ are hydrogen;-   ll) a compound wherein R¹ is —NHR²² wherein R²² is —CH₂CH₂N(CH₂CH₃)₂    or ethylmorpholinyl, R³is ethyl, and R⁴, R⁵ and R⁶ are hydrogen;-   mm) a compound wherein R¹ is —NHNH₂, R³is hydrogen, alkyl, or    phenyl, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   nn) a compound wherein R¹ is —NHR²² wherein R²² is NH₂, —CH₂CH₂OH,    CH₂CH(OH)(CH₃), ethylmorpholinyl, ethylmorpholinyl substituted with    ═O, ethylphenyl, —CH₂CH₂NHCH₃, —CH₂CH₂N(—CH₂CH₂CH₃)₂,    ethylpiperidinyl, or ethylpiperidinylbenzyl, R² is methyl, and R³,    R⁴, R⁵ and R⁶ are hydrogen;-   oo) a compound wherein R¹ is morpholinyl, R² is —C(F)₃, —C(═O),    —CH₂OH, —C(═O)H, —COOH, chloro, —NO₂, or cyano, and R³, R⁴, R⁵ and    R⁶ are hydrogen;-   pp) a compound wherein R¹ is —NHR²² wherein R²² is heptyl, phenyl,    benzyl, or ethylphenyl, R² is hydrogen, methyl, or chlorophenyl, R⁴,    R⁵ and R⁶ are hydrogen;-   qq) a compound wherein R¹ is —NR²¹ wherein R²¹ is phenyl and R², R³,    R⁴, R⁵ and R⁶ are hydrogen;-   rr) a compound wherein R¹ is morpholinyl and R², R³, R⁴, R⁵ and R⁶    are hydrogen;-   ss) a compound wherein R¹ is methylpiperazinyl and R², R³, R⁴, R⁵    and R⁶ are hydrogen;-   tt) a compound wherein R¹ is —NHCH₂CH₂OH or NHCH₂CH₂OCH₃, R² is    phenyl and R³, R⁴, R⁵ and R⁶ are hydrogen;-   uu) a compound wherein R¹ is —NHR²² wherein R²² is ethylamino,    butylamino, ethylaminomethyl, and R² is hydrogen, methyl, or    —C(═O)NHR², and R³, R⁴, R⁵ and R⁶ are hydrogen;-   vv) a compound wherein R¹ is is —NHR²² wherein R² is    ethylpiperidinyl, methylpiperidinylbenzyl, piperidinylbenzyl,    ethylpiperidinylbenzyl, methylpyrrolidinylmethyl,    ethylpiperazinylbenzyl, —CH₂C(═O)-piperazinylbenzyl,    —C(═O)-methylnaphthyl, —CH₂CH₂CH₂CH₂CH₂N(CH₃)(C₇H₇),    —CH₂C(═O)-piperidinylbenzyl, —C(═O)-methylpiperidinylbenzyl, or    —CH(CH₃)₂, and R³, R⁴, R⁵ and R⁶ are hydrogen;-   ww) a compound wherein R¹ is —CHCH₂CH₂-isoquinolinyl,    —NHCH₂CH₂N(CH₂CH₂CH₃)₂, propyl substituted with piperidinyl fused to    phenyl, —NHCH₂CH₂, or —NHCH₂CH₂CH₂CH₂CH₂ substituted with a    piperidinyl fused to two adjacent carbon atoms of a phenyl moiety;-   xx) a compound wherein R¹ is —NH substituted with two pyrrolidinyl    groups; R³is methyl, and R², R⁴, R⁵ and R⁶ are hydrogen:-   yy) a compound wherein R¹ is —COOCH₃, R³is methyl, and R³, R⁴, R⁵    and R⁶ are hydrogen;-   zz) a compound wherein R¹ is hydrogen, R² is methyl, R⁷ is oxygen;-   aaa) a compound wherein R⁷ is methyl or oxygen, and R¹, R², R⁴, R⁵    and R⁶ are hydrogen;-   bbb) a compound wherein R¹ is —NHCH₂CH₂N(CH₂CH₃)₂, R³ is ethyl, and    R², R⁴, R⁵ and R⁶ are hydrogen; and-   ccc) a compound wherein R¹ is —NHCH₂CH(OH)(CH₃) or    —NHCH₂CH₂NHCH₂CH₂OH, R² methyl, and R³, R⁴, R⁵ and R⁶ are hydrogen.

In an aspect, a compound of the Formula I is provided wherein: (a) R¹ isoptionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, cyano,amino, cycloalkyl, -sulfonyl, sulfinyl, sulfenyl, thioaryl, thioalkyl,carbonyl, silyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,—SR²⁴ wherein R²⁴ is optionally substituted alkyl, carbonyl, carboxyl,carbamoyl, aryl, heterocylic, or heteroaryl; (b) R² is optionallysubstituted halo, hydroxyl, alkyl, alkenyl, alkoxy, carbonyl, carboxyl,phenyl, benzyl, amino, aryl, cyano, —COH, piperazinyl, alcohol,piperidinyl, morpholinyl, or naphthyl; (c) R³ is hydrogen, halo,hydroxyl, alkyl, alkenyl, alkoxy, phenyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiol, sulfenyl, sulfonyl, sulfinyl, ornitro; (d) R⁴ is hydrogen, halo, or nitro (e) R⁵ is hydrogen, halo,alkoxy, or amido: (f) R⁷ is hydrogen halo, hydroxyl, alkyl, alkenyl,alkoxy, carboxy, morpholino; imidazolyl; piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl or R⁷ is absent and there is a double bondbetween N at position 1 and C at position 6; and/or (g) R¹ and R², R¹and R⁷ or R² and R³ may form a heteroaryl or heterocyclic ring.

In another aspect of the invention a compound of the Formula I isprovided wherein R¹ is Cl or Br, —NH₂, alkyl, —CN, ═S, silyl, sulfonyl,thioalkyl, thioaryl, piperazinyl, piperazinyl, piperidinyl, piperidinyl,morpholinyl, pyrrolidinyl, pyrrolyl, or pyrrolidinyl, which may beoptionally substituted with halo, ═O, alkoxy, alkenyl, alkyl,substituted alkyl, —CN, —SR²⁴ wherein R²⁴ is optionally substitutedmethyl, ethyl, phenyl, heterocyclic, or heteroaryl, or —CO substitutedwith phenyl or substituted phenyl.

In another aspect of the invention a compound of the Formula I isprovided wherein R² is carbonyl, piperazinyl, morpholinyl, sulfonyl,sulfinyl, sulfenyl, or phenyl, —CN, —COH, CH₂OH, —OCH₂CH₃, or alkylwhich may be optionally substituted with alkyl, alkoxy, amino, halo,phenyl, substituted phenyl, benzyl, hydroxyl, amino, piperidinyl, ormorpholinyl.

In another aspect of the invention a compound of the Formula I isprovided wherein R³ is piperazinyl; substituted piperzinyl; alkyl whichmay optionally be substituted with amino; phenyl; substituted phenyl;amino which may be optionally substituted with alkyl or alkylamine(e.g., NHCOOC(CH₃)₃), carboxyl, or substituted carboxyl; hydroxyl; ornitro.

In another aspect of the invention a compound of the Formula I isprovided wherein R⁴ is nitro or hydrogen.

In another aspect of the invention a compound, of the Formula I isprovided wherein R⁵ is hydrogen, halo, —OCH₂CH₂CH₂NHCOOC(CH₃)₃, or—OCH₃.

In another aspect of the invention a compound of the Formula I isprovided wherein R⁷ is alkyl, morpholinyl, benzyl, imidazolyl,—CH₂COOCH₂CH₃, CH₂C═COOCH₂CH₃, CH₂CH₂CH₂SO₂OH, CH₂CH₂CH₂SO₃ ⁻,CH₂CH₂CH₂CH₂PO(OH)₂, or CH₂CH₂CH₂PO(OH)₂.

In another aspect of the invention a compound of the Formula I isprovided wherein R⁷ is absent and there is a double bond between N atposition 1 and C at position 6.

In a further aspect, a compound of the Formula I is provided wherein R¹,R², R³, and R⁷ are independently substituted aliphatic, lower alkylsubstituted amino, lower alkyl substituted halogen, cycloaliphatic, orsubstituted cycloaliphatic.

In a still further aspect the invention a compound of the Formula I isprovided wherein R¹ is a piperazinyl which may be substituted (e.g.,with a pyrimidinyl moiety); halo; amino which may be substituted; cyano;—SR²⁴ wherein R²⁴ is alkyl or aryl (e.g. phenyl) which may besubstituted (e.g., halo); substituted alkyl [e.g., alkyl substitutedwith halogen, such as CH(Br)₂]; morpholinyl; pyrrolyl which may besubstituted; hydroxyl: —OR³⁵ wherein R³⁵ is alkyl; —C═CHR³⁶ wherein R³⁶is alkyl; or pyrrolidinyl.

In a still further aspect the invention a compound of the Formula I isprovided wherein R² is hydrogen; morpholinyl; piperazinyl which may besubstituted (e.g., with a pyrimidinyl moiety); phenyl; alkyl; alkoxy(e.g. CH(OCH₃)₂); substituted alkyl; substituted aryl (e.g., phenyl);cyano; or hydroxyl.

In a still further aspect the invention a compound of the Formula I isprovided wherein R³ is hydrogen; hydroxyl; alkyl which may besubstituted (e.g., halo); amino which may be substituted; —COR³⁷ whereinR³⁷ is hydrogen, hydroxyl, alkoxy (e.g. —OCH₃); or, aryl (e.g. phenyl)which may be substituted (e.g., alkyl).

In a still further aspect the invention a compound of the Formula I isprovided wherein R⁴ is hydrogen or halo; R⁵ is hydrogen or halo; R⁶ ishydrogen or halo.

In a still further aspect the invention a compound of the Formula I isprovided wherein R⁷ is hydrogen; alkyl which may be substituted (e.g.with phenyl); —CH₂CH₂COOR³⁸ wherein R³⁸ is alkyl, —CH₂C═COOR³⁸ whereinR³⁸ is alkyl, CH₂CH₂CH₂S(O)₂OH, morpholinyl, benzyl, imidazolyl, or[CH₂]_(n)PO(OH)₂ wherein n is 1 to 6, in particular 3 or 4.

In a still further aspect the invention a compound of the Formula I isprovided wherein R¹ and R² form a piperidinyl ring which may optionallybe substituted with a carboxyl.

In a still further aspect the invention a compound of the Formula I isprovided wherein R¹ and R⁷ form a pyrimidinyl ring which may optionallybe substituted with alkyl, aryl, halo, or hydroxyl.

In a particular aspect R¹ is —NR²¹R²² wherein R²¹ is hydrogen, and R²²is hydrogen, alkyl, carbonyl, aryl, amino, cycloalkane, heterocylic, orheteroaryl which may be substituted. In embodiments R²² may comprise orbe selected from the group consisting of hydrogen, C₁-C₆ alkyl (e.g.methyl or ethyl) which may be substituted with optionally substitutedhydroxyl, alkyl, amino, carbonyl, carboxyl, morpholinyl, isoquinolinyl,or an amino which may be substituted with one or more of optionallysubstituted alkyl, benzyl, carboxyl, alcohol group, heteroaryl orheterocyclic, a propanol group, phenyl which may be optionallysubstituted with halo, benzyl which may be substituted with alkoxy,cyclohexyl, piperidinyl which may be substituted with optionallysubstituted phenyl, pyrrolidinyl or pyrrolidinylalkyl which may besubstituted with alkyl, —COOR⁴⁰ wherein R⁴⁰ is alkyl which may besubstituted, or [CH₂]_(m)-piperidinyl wherein m is 1 to 4, in particular1 to 3 and the piperidinyl is optionally substituted with optionallysubstituted alkyl, phenyl or benzyl.

In embodiments, R²² is —R⁶⁰R⁶¹ wherein R⁶⁰ is —NH[CH₂]_(w)NH wherein wis 1 to 4, in particular 2 or 3, and R⁵¹ is piperazinyl substituted withpyrimidinyl which may be substituted, in particular substituted withalkyl.

In embodiments, R²² is —R⁶²R⁶³ wherein R⁶² is —[CH₂]_(w)N(CH₃) wherein wis 1 to 4, in particular 2 or 3, and R⁶³ is piperazinyl substituted withpyrimidinyl which may be substituted, in particular substituted withalkyl.

In an aspect of the invention, a compound of the Formula I is providedwherein R¹ is halo especially chloro or bromo, R² is alkyl which may besubstituted, in particular substituted with alkoxy (e.g., methoxy,dimethoxy), substituted aryl which may be substituted with alkyl,alkoxy, (e.g., benzyl, methoxy phenyl), halo (e.g. bromo or chloro), orcarbonyl, a substituted or unsubstituted saturated 3 to 6-memberedheteromonocylic group containing 1 to 4 nitrogen atoms [e.g.,piperidinyl, and piperazinyl] or a saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g. morpholinyl; sydnonyl], in particular a substitutedmorpholinyl, piperazinyl,or piperazinyl substituted with a heteroaryl inparticular an unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl,pyrimidinyl, pyrazinyl, or pyridazinyl, especially pyrimidinyl, andoptionally R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In another aspect of the invention, a compound of the Formula I isprovided wherein R¹ is halo especially chloro or bromo, and R³ is asubstituted or unsubstituted saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms [e.g., piperidinyl, andpiperazinyl] or a saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl; sydnonyl], in particular a substituted morpholinyl,piperazinyl, or piperazinyl substituted with alkyl or a heteroaryl inparticular an unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl,pyrimidinyl, pyrazinyl, or pyridazinyl, especially pyrimidinyl, or R² isa substituted amino, in particular amino substituted with alkyl orsubstituted alkyl, in particular alkyl substituted with alkoxy carbony,and optionally R², R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In further aspect R¹ is halo, especially bromo or chloro, and R² andR³form an unsaturated ring, in particular phenyl, R⁵ is a heteroaryl, inparticular a substituted or unsubstituted unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, especially imidazolyl, andoptionally R⁴, R⁶ and R⁷ are hydrogen.

In a further aspect, R¹ is halo, especially bromo or chloro, and R⁴ isnitro, and optionally R², R³, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect, the invention provides a compound of the Formula Iwherein R¹ is a thiol substituted with alkyl (thioalkyl); substitutedalkyl, in particular alkyl substituted with a substituted orunsubstituted saturated 3 to 6-membered heteromonocylic group containing1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,and piperazinyl] or a saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl; sydnonyl], especially a substituted morpholinyl orpiperidinyl; aryl; substituted aryl; carboxyl which may be substitutedwith substituted or unsubstituted aryl; optionally R² is alkyl, inparticular lower alkyl; optionally R³ is alkyl, in particular loweralkyl or nitro; optionally R⁵ is alkoxy; optionally R⁷ is alkyl; andoptionally R⁴, R⁵, and R⁶, are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is ═S, and optionally R² is alkyl, in particularlower alkyl, R⁵ is alkoxy, and R³, R⁴, R⁶ and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is sulfonyl which may be substituted withsubstituted or unsubstituted aryl, in particular substituted phenyl, andoptionally R² is alkyl and R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is substituted or unsubstituted alkyl or alkynyl, inparticular alkyl substituted with aryl, substituted aryl, halo, cyano,or alkynyl substituted with alkyl; and optionally R² is alkyl, R⁷ isalkyl, and R³, R⁴, R⁵ and R⁶ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is cyano and R² is aryl or alkyl, and optionally R³,R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein one or both of R¹ and R² are a saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially asubstituted morpholinyl, and optionally R³, R⁴, R⁵, R⁶, and R⁷ arehydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is a saturated 3 to 6-membered heteromonocylic groupcontaining 1 to 4 nitrogen atoms [e.g. pyrrolidinyl], which may besubstituted with substituted or unsubstituted carboxyl; R² is alkyl orhalo, and optionally R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is hydroxyl; R² is alkyl or substituted alkyl or R³is a saturated 3 to 6-membered heteromonocylic group containing 1 to 4nitrogen atoms [e.g. piperidinyl, and piperazinyl] which may optionallybe substituted with a heteroaryl [e.g., pyrimidinyl], and the other ofR² or R³ is hydrogen, and optionally R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is a saturated 3 to 6-membered heteromonocylic groupcontaining 1 to 4 nitrogen atoms [e.g., piperidinyl and piperazinyl]which may be substituted with carboxyl or carboxyl substituted withalkyl or alkoxy or with purinyl or substituted purinyl; R² is alkyl orsubstituted alkyl, in particular alkylaryl, and optionally R³, R⁴, R⁵,R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is ═O, and R² is alkyl, alkylaryl, cyano, alkoxy, orsubstituted alkoxy, and optionally R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is alkoxy, R² is alkyl, substituted alkyl, oralkoxy, and optionally R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ and R² form a heterocyclic, in particular asaturated 3 to 6-membered heteromonocylic group containing 1 to 4nitrogen atoms, in particular a 6-membered ring comprising 1 or 2nitrogen atoms [e.g., piperidinyl and piperazinyl] which may besubstituted for example with alkyl, halo, carboxyl, or alkoxy carbonyl,and optionally R³, R⁴, R⁵, R⁶, and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ and R⁷ form a heteroaryl, in particular anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl, R² is hydrogen or alkyl, and R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen.

In a further aspect of the invention, a compound of the Formula I isprovided wherein R¹ is silyl which may be substituted, in particularsubstituted with alkyl R² is alkyl, and R³, R⁴, R⁵, R⁶, and R⁷ arehydrogen.

In an embodiment, R¹ is a piperazinyl or substituted piperazinyl, inparticular a piperazinyl substituted with a pyrimidinyl of the FormulaII below.

Thus, the invention also provides an isolated and pure, in particular,substantially pure, compound, of the Formula II wherein one or both ofR¹⁰ and R¹¹ are independently substituted or unsubstituted hydrogen,hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy,alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl,heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl,amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro,ureido, cyano, halo, silyl, silyalkyl, silyloxy, silylthio, ═O, ═S,carboxyl, carbonyl, or carbamoyl, or an isomer or a pharmaceuticallyacceptable salt thereof.

In an aspect of the compound of the Formula II is provided wherein R¹⁰is hydrogen; hydroxyl; alkyl; aryl [e.g. phenyl which is optionallysubstituted (e.g., halide)]; piperazinyl which may be substituted (e.g.substituted with a pyrimidinyl); —NR⁵⁵R⁵⁶ wherein R⁵⁵ is hydrogen oralkyl, and R⁵⁶ is phenyl which may be substituted or alkyl which may besubstituted (e.g. amino, in particular —CH₂CH₂NH₂; CH₂CH₂NHCOOC(CH₃)₃);morpholinyl which may be substituted; or —S R²⁵ wherein R²⁵ is phenylwhich may be substituted; and R¹¹ is hydrogen, or aryl (e.g. phenyl)which may be substituted.

In a particular aspect of the invention a compound of the Formula II isprovided wherein R¹⁰ is hydrogen, halo, optionally substituted hydroxyl,alkyl, pyridinyl, phenyl, benzyl, piperazinyl, amino, morpholinyl, or —SR²⁴ wherein R²⁴ is alkyl or aryl. In an embodiment, R¹⁰ is—NH[CH₂]_(m)NR⁶⁰R⁶¹ wherein m is 1 to 6, in particular 2 to 4, R⁶⁰ ishydrogen, R⁶¹ is a carboxyl, in particular —COOC(CH₃)₃.

In an aspect of the invention a compound of the Formula II is providedwherein R¹¹ is hydrogen, halo, optionally substituted alkyl, pyridinyl,piperidinyl, morpholinyl, piperazinyl, or phenyl.

In another aspect, of the invention a compound of the Formula II isprovided wherein both of R¹⁰ and R¹¹ are not hydrogen.

In particular embodiments of the invention one or more of R¹⁰ and R¹¹are alkyl, in particular C₁-C₆ alkyl and the other of R¹⁰ and R¹¹ ishydrogen.

In particular embodiments of the invention one or more of R¹⁰ and R¹¹are aryl in particular phenyl or benzyl and the other of R¹⁰ and R¹¹ ishydrogen.

In particular embodiments of the invention a compound of the Formula IIis a compound in Table 3, more particularly MW01-2-065LKM,MW01-2-069SRM, MW01-2-151SRM, MW01-5-188WH, MW01-6-127WH, MW01-6-189WH,MW01-7-107WH, and derivatives thereof.

The invention also provides an isolated and pure, in particular,substantially pure, compound of the Formula III wherein R¹⁵ and R¹⁶ areindependently substituted or unsubstituted hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylthio, ═O, ═S, carboxyl, carbonyl, orcarbamoyl, or an isomer or pharmaceutically acceptable salt thereof.

The invention also provides an isolated and pure, in particular,substantially pure, compound, of the Formula IV wherein R⁷⁰ and R⁷¹ areindependently substituted or unsubstituted hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylthio, ═O, ═S, carboxyl, carbonyl, orcarbamoyl, or an isomer or pharmaceutically acceptable salt thereof.

In an aspect, the invention relates to a compound of the Formula IVwherein R⁷⁰ is a heterocylic, in particular a saturated 3 to 6-memberedheteromonocylic group containing 1 to 4 nitrogen atoms moreparticularly, pyrrolidinyl, imidazolidinyl, piperidinyl, andpiperazinyl, especially piperazinyl or piperidinyl, which may besubstituted with alkyl especially methyl, dimethyl, cycloalkylespecially cyclohexyl, aryl especially phenyl, a substituted orunsubstituted unsaturated condensed heterocyclic group containing 1 to 5nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl,indazolyl, quinazolinyl, pteridinyl, quinolizidinyl, phthalazinyl,naphthyridinyl, quinoxalinyl, cinnolinyl, phenanthridinyl, acridinyl,phenanthrolinyl, phenazinyl, carbazolyl, purinyl, benzimidazolyl,quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, or indazolyl,especially benzimidazolyl substituted with oxy.

The invention also relates to a compound of the Formula IV wherein R⁷⁰is amino or substituted amino, and optionally R⁷¹ is aryl, in particularphenyl. In an aspect R⁷⁰ is —N—R²² wherein R²¹ is hydrogen or alkyl, inparticular C₁-C₆ alkyl, more particularly methyl or dimethyl, or—N—R²¹R²²wherein R²¹ is hydrogen or alkyl, in particular C₁-C₆ alkyl,more particularly methyl and R²² is alkyl substituted with amino orsubstituted amino, heterocyclic, substituted heterocylic, or cycloalkyl.In an embodiment, R⁷⁰ is —N—R²¹R²² wherein R²¹ is hydrogen or alkyl, inparticular C₁-C₆ alkyl, more particularly methyl and R²² is C₁-C₆ alkyl,especially methyl or ethyl substituted with a cycloalkyl especiallycyclopropyl, a heterocyclic especially piperidinyl, pyrrolidinyl, ormorpholinyl which may be substituted in particular substituted witharyl, especially benzyl.

A compound of the Formula IV may comprise structure 124, 125, 126, 127,128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, or 139 in Table 5or derivatives thereof.

The invention also provides an isolated and pure, in particular,substantially pure, compound of the Formula V wherein R⁵⁰ and R⁵¹ areindependently substituted or unsubstituted hydrogen, hydroxyl, alkyl,alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl,cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl,heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino,azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,halo, silyl, silyloxy, silylthio, ═O, ═S, carboxyl, carbonyl, orcarbamoyl, or an isomer or pharmaceutically acceptable salt thereof.

The invention relates to a compound of the Formula V wherein R⁵⁰ issubstituted or unsubstituted hydrogen, alkyl, aryl, or heterocyclic; R⁵¹is substituted or unsubstituted hydrogen or alkyl, and R⁵² issubstituted or unsubstituted hydrogen, alkyl, cycloalkyl, heteroaryl orhalo. In an aspect, the invention relates to a compound of the Formula Vwherein R⁵⁰ is hydrogen, C₁-C₆ alkyl which may be substituted withalkyl, especially methyl or trimethyl, phenyl, or a 3 to 6-memberedheteromonocylic group containing 1 to 4 nitrogen atoms moreparticularly, piperidinyl or morpholinyl, R⁵¹ is hydrogen or alkylespecially methyl, and R⁵² is hydrogen, alkyl especially methyl,dimethyl, ethyl, or propyl, cyclohexyl, chloro, or an unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl,especially pyridinyl. In an embodiment, R⁵⁰ is aryl, R⁵¹ is hydrogen,and R⁵² is C₁-C₆ alkyl.

A compound of the Formula V may comprise compound MW01-7-057WH, orstructure 32, 34, 36, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 63,69, 70, 71, 75, 76, 77, 78, 79, 80, 81, and 82 in Table 5 or derivativesthereof

In some embodiments, the present invention, provides novel organiccompounds, and/or heterocyclic derivatives thereof, depicted in Tables2, 3, 4 or 5.

Derivative groups that may be used to modify the compounds of theFormula I, II, III, IV, or V can be found in U.S. Patent Application No.20030176437 (herein incorporated by reference in its entirety for allpurposes).

A compound of the Formula I, II, III, IV, or V may be in the form of aprodrug that is converted in vivo to an active compound. For example, ina compound of the Formula I one or more of R¹, R², R3, R⁴, R⁵, R⁶, andR⁷ may comprise a cleavable group that is cleaved after administrationto a subject to provide an active (e.g., therapeutically active)compound, or an intermediate compound that subsequently yields theactive compound. A cleavable group can be an ester that is removedeither enzymatically or non-enzymatically.

A compound of the Formula I, II, III, IV, or V may comprise a carrier,such as one or more of a polymer, carbohydrate, peptide or derivativethereof, which may be directly or indirectly covalently attached to thecompound. A carrier may be substituted with substituents describedherein including without limitation one or more alkyl, amino, nitro,halogen, thiol, thioalkyl, sulfate, sulfonyl, sulfinyl, sulfoxide,hydroxyl groups. In aspects of the invention the carrier is an aminoacid including alanine, glycine, praline, methionine, serine, threonine,asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl. A carriercan also include a molecule that targets a compound of the Formula I,II, III, IV, or V to a particular tissue or organ. Thus, a carrier mayfacilitate or enhance transport of a compound of the Formula I, II, III,IV or V to the brain.

Process

Compounds of the Formula I, II, III, IV, or V can be prepared usingreactions and methods generally known to the person of ordinary skill inthe art, having regard to that knowledge and the disclosure of thisapplication including the Examples. The reactions are performed in asolvent appropriate to the reagents and materials used and suitable forthe reactions being effected. It will be understood by those skilled inthe art of organic synthesis that the functionality present on thecompounds should be consistent with the proposed reaction steps. Thiswill sometimes require modification of the order of the synthetic stepsor selection of one particular process scheme over another in order toobtain a desired compound of the invention. It will also be recognizedthat another major consideration in the development of a synthetic routeis the selection of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe skilled artisan is Greene and Wuts (Protective Groups In OrganicSynthesis, Wiley and Sons, 1991).

The starting materials and reagents used in preparing compounds or theinvention are either available from commercial suppliers or are preparedby methods well known to a person of ordinary skill in the art,following procedures described in such references as Fieser and Fieser'sReagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, NewYork, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 andsupps., Elsevier Science Publishers, 1989; Organic Reactions, vols.1-40, John Wiley and Sons, New York, N.Y., 1991; March J.: AdvancedOrganic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; andLarock: Comprehensive Organic Transformations, VCH Publishers, New York,1989.

The starting materials, intermediates, and compounds of the Formula I,II, III, IV, or V may be isolated and purified using conventionaltechniques, such as precipitation, filtration, distillation,crystallization, chromatography, and the like. The compounds of theFormula I, II, III, IV, or V may be characterized using conventionalmethods, including physical constants and spectroscopic methods, inparticular HPLC.

The compounds of the Formula I, II, III, IV, or V which are basic innature can form a wide variety of different salts with various inorganicand organic acids. In practice is it desirable to first isolate acompound of the Formula I, II, III, IV, or V from the reaction mixtureas a pharmaceutically unacceptable salt and then convert the latter tothe free base compound by treatment with an alkaline reagent andsubsequently convert the free base to a pharmaceutically acceptable acidaddition salt. The acid addition salts of the base compounds of theFormula I, II, III, IV, or V are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

Compounds of the Formula I, II, III, IV, or V which are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. These salts may be prepared by conventionaltechniques by treating the corresponding acidic compounds with anaqueous solution containing the desired pharmacologically acceptablecations and then evaporating the resulting solution to dryness,preferably under reduced pressure. Alternatively, they may be preparedby mixing lower alkanolic solutions of the acidic compounds and thedesired alkali metal alkoxide together and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are typically employed toensure completeness of reaction and maximum product yields.

In particular aspects, the present invention provides methods of makingthe compounds disclosed herein, comprising the steps provided (See,e.g., the Figures and Materials and Methods). Broad Process Descriptionfor Pyr PCT Application

In an aspect, the invention provides a process for preparing a compoundof the formula II wherein R11 is hydrogen and R10 is an unsaturated 5 to6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, or tetrazolyl, more particularly pyridinyl, which comprisesreacting a compound of the formula II wherein R10 is halo, in particularchloro, and R11 is hydrogen, with boronic acid substituted with anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularlypyridinyl, under suitable conditions to prepare a compound of theformula II wherein R11 is hydrogen and R10 is an unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, or tetrazolyl, more particularly pyridinyl. In an embodiment,R10 is phenyl substituted with halo.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R11 is hydrogen, and R10 is asubstituted aryl which comprises reacting a compound of the formula IIwherein R10 is halo, in particular chloro, and R11 is hydrogen, with asubstituted aryl boronic acid under suitable conditions to prepare acompound of the formula II wherein R11 is hydrogen and R10 is asubstituted aryl. In an embodiment, R10 is phenyl substituted with halo.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is alkylwhich comprises reacting a compound of the formula II wherein R11 ishalo, in particular chloro, and R10 is hydrogen, with an alkyl boronicacid under suitable conditions to prepare a compound of the formula IIwherein R10 is hydrogen and R11 is alkyl. In an embodiment, R11 is loweralkyl, in particular methyl or ethyl, and a compound of the formula IIwherein R11 is chloro is reacted with lower alkyl boronic acid, inparticular methyl or ethyl boronic acid under suitable conditions.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is an alkylwhich comprises reacting a pyridazine substituted at the C3 positionwith halo (e.g., chloro), at the C4 position with alkyl, and at the 6position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine undersuitable conditions to prepare a compound of the formula II wherein R10is hydrogen and R11 is an alkyl. In an embodiment, R11 is methyl orethyl.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is aryl whichcomprises reacting a compound of the formula II wherein R10 is hydrogenand R11 is halo (e.g., chloro), with pyridazine substituted at the C3position with halo (e.g., chloro), at the C4 position with aryl, and atthe 6 position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine undersuitable conditions to prepare a compound of the formula II wherein R10is hydrogen and R11 is aryl. In an embodiment, R11 is phenyl.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularlypyridinyl which comprises reacting a compound of the formula II whereinR11 is halo, in particular chloro, and R10 is hydrogen, with a boronicacid substituted with an unsaturated 5 to 6 membered heteromonocyclylgroup containing 1 to 4 nitrogen atoms, in particular, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, ortetrazolyl, more particularly pyridinyl, under suitable conditions toprepare a compound, of the formula II wherein R10 is hydrogen and R11 isan unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularlypyridinyl.

In an embodiment, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is pyridinylwhich comprises reacting a compound of the formula II wherein R11 ishalo, in particular chloro, and R10 is hydrogen, with a pyridinylboronic acid under suitable conditions to prepare a compound of theformula II wherein R10 is hydrogen and R11 is pyridinyl.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularlypyridinyl which comprises reacting a pyridazine substituted at the C3position with halo, at the C4 position with an unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, or tetrazolyl, more particularly pyridinyl, and at the 6position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine undersuitable conditions to prepare a compound of the formula II wherein R10is hydrogen and R11 is an unsaturated 5 to 6 membered heteromonocyclylgroup containing 1 to 4 nitrogen atoms, in particular, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, ortetrazolyl, more particularly pyridinyl.

In an embodiment, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 is pyridinylwhich comprises reacting a pyridazine substituted at the C3 positionwith halo, at the C4 position with pyridinyl, and at the 6 position withphenyl, with 2-(piperidin-4-yloxy)pyrimidine under suitable conditionsto prepare a compound of the formula II wherein R10 is hydrogen and R11is pyridinyl.

In another aspect, the invention provides a process for preparing acompound of the formula II wherein R10 is hydrogen and R11 ispiperidinyl or substituted piperidinyl which comprises reacting acompound of the formula II wherein R11 is halo, in particular chloro,and R10 is hydrogen with piperazinyl or substituted piperazinyl undersuitable conditions to prepare a compound of the formula II wherein R10is hydrogen and R11 is piperidinyl or substituted piperidinyl.

In another aspect, the invention provides a process for preparing acompound of the formula I wherein R1 is piperazinyl or piperazinylsubstituted with alkyl, aryl, or cycloalkyl, R2 is aryl, R3, R4, R5 andR6 are hydrogen and R7 is absent, which comprises reacting a pyridazinesubstituted at the C3 position with halo, at the C4 position with arylwith a piperazinyl or piperazinyl substituted with alkyl, aryl, orcycloalkyl, under suitable conditions to prepare a compound of theformula I wherein R1 is piperazinyl or piperazinyl substituted withalkyl, aryl, or cycloalkyl, R2 is aryl, R3, R4, R5 and R6 are hydrogenand R7 is absent.

In another aspect, the invention provides a process for preparing acompound of the formula I wherein R1 is piperazinyl or piperazinylsubstituted with alkyl, aryl, or cycloalkyl, R2 is an unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, inparticular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, or tetrazolyl, more particularly pyridinyl, R3, R4, R5 and R6are hydrogen and R7 is absent, which comprises reacting a pyridazinesubstituted at the C3 position with halo, at the C4 position with anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularlypyridinyl, with piperazinyl or piperazinyl substituted with alkyl, aryl,or cycloalkyl under suitable conditions to prepare a compound of theformula I wherein R1 is piperazinyl or piperazinyl substituted withalkyl, aryl, or cycloalkyl, R2 is an unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, ortetrazolyl, more particularly pyridinyl, R3, R4, R5 and R6 are hydrogenand R7 is absent.

In another aspect, the invention provides a process for preparing acompound of the formula I wherein R1 is substituted amino in particularamino substituted with substituted morpholinyl, in particularmorpholinoethyl, R2 is aryl or an unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, ortetrazolyl, in particular pyridinyl, R3, R4, R5 and R6 are hydrogen andR7 is absent, which comprises reacting a pyridazine substituted at theC3 position with halo, at the C4 position with aryl or an unsaturated 5to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms,in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl, or tetrazolyl, more particularly pyridinyl, with substitutedamino in particular amino substituted with substituted morpholinyl, inparticular morpholinoethyl, under suitable conditions to prepare acompound of the formula I wherein R1 is substituted amino in particularamino substituted with substituted morpholinyl, R2 is aryl, R3, R4, R5and R6 are hydrogen and R7 is absent.

In another aspect, the invention provides a process for preparing acompound of the formula V wherein R50 is aryl, R51 is hydrogen, and R52is alkyl comprising reacting a pyridazine substituted at position C3with halo, at position C4 with aryl and position 6 with alkyl with1-(2-pyrimidyl)piperazine under suitable conditions to prepare acompound of the formula V wherein R50 is aryl, R51 is hydrogen, and R52is alkyl.

In another aspect, the invention provides a process for preparing acompound of the formula I wherein R1 is substituted amino, R2 is anunsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, in particularpyridinyl, R3, R4, R5 and R6 are hydrogen and R7 is absent comprisingreacting a pyridazine substituted at the C3 position with halo, at theC4 position with an unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, inparticular pyridinyl, and at the C6 position phenyl, and a substitutedamino under suitable conditions to prepare a compound of the formula Iwherein R1 is substituted amino, R2 is an unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, ortetrazolyl, in particular pyridinyl, R3, R4, R5 and R6 are hydrogen andR7 is absent.

In the preparation of compounds of the Formula II, a key precursor (See,e.g., FIG. 1) that may be utilized was obtained commercially and useddirectly for the synthesis of the illustrated compound MW01-3-183WHwithout further purification. Compounds may be synthesized with yieldsof 81-96%. All purified compounds may be characterized by HPLC, massspectrometry and NMR in order to confirm syntheses. In FIG. 1, asynthetic scheme is shown, for synthesis of MWO1-3-183WH withunconstrained aromatic ring at position 6 and no modification atposition 5. Reagent and condition; (a) 1-BuOH, NH₄Cl,2-(piperazin-1-yl)pyrimidine.

Thus, in an aspect, the invention provides a method for preparing acompound of the Formula II wherein a substituted 6-phenylpyridazine isreacted with 2-(piperazin-1yl)pyridmidine to produce a compound of theFormula II wherein R¹⁰ and R¹¹ are hydrogen. A compound of the formulaII wherein R10 and R11 are hydrogen can be reacted under suitableconditions and with suitable reagents to introduce the radicals R¹⁰ andR¹¹ which are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl,aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl,acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azido, thiol,thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl,silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl,or carboxamide

Therapeutic efficacy and toxicity of compounds, compositions and methodsof the invention may be determined by standard pharmaceutical proceduresin cell cultures or with experimental animals such as by calculating astatistical parameter such as the ED₅₀ (the dose that is therapeuticallyeffective in 50% of the population) or LD₅₀ (the dose lethal to 50% ofthe population) statistics. The therapeutic index is the dose ratio oftherapeutic to toxic effects and it can be expressed as the ED_(50/)LD₅₀ratio. Pharmaceutical compositions which exhibit large therapeuticindices are preferred. By way of example, one or more of the therapeuticeffects, in particular beneficial effects disclosed, herein, can bedemonstrated in a subject or disease model, for example, a TgCRND8 mousewith symptoms of Alzheimer's disease.

Biological investigations were done with compounds disclosed herein thatwere >95% homogenous as determined by HPLC/MS analysis. As part of ahierarchal, cell-based screening protocol, the compounds were screenedfor their ability to block IL-1β and TNFα production by BV-2 mousemicroglial cells stimulated with LPS. The data for MW01-3-183WH isshown, in FIG. 2. Derivative groups that may be used to modify thecompounds of the present invention can be found in U.S. PatentApplication No. 20030176437 (herein incorporated by reference in itsentirety for all purposes).

The compounds disclosed herein can be tested for liver toxicity which isan important initial consideration for orally administered compoundssince the liver is the major site of initial drug metabolism and iscritical to overall metabolism and homeostasis of an animal. An exampleof an in vivo liver toxicity test in animals is illustrated in Example2. Compounds disclosed herein may also be tested for cardiac safety bytesting for hERG channel inhibition, for example using the methodillustrated in Example 3.

Compositions and Kits

A compound of the Formula I, II, III, IV, or V of the invention may beformulated into a pharmaceutical composition for administration to asubject. Pharmaceutical compositions of the present invention orfractions thereof comprise suitable pharmaceutically acceptablecarriers, excipients, and vehicles selected based on the intended formof administration, and consistent with conventional pharmaceuticalpractices. Suitable pharmaceutical carriers, excipients, and vehiclesare described in the standard text, Remington's Pharmaceutical Sciences,Mack Publishing Company (Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., USA 1985). By way of example for oraladministration in the form of a capsule or tablet, the active componentscan be combined with an oral, non-toxic pharmaceutically acceptableinert carrier such as lactose, starch, sucrose, methyl cellulose,magnesium stearate, glucose, calcium sulfate, dicalcium phosphate,mannitol, sorbital, and the like. For oral administration in a liquidform, the drug components may be combined with any oral, non-toxic,pharmaceutically acceptable inert carrier such as ethanol, glycerol,water, and the like. Suitable binders (e.g. gelatin, starch, cornsweeteners, natural sugars including glucose; natural and syntheticgums, and waxes), lubricants (e.g. sodium oleate, sodium stearate,magnesium, stearate, sodium benzoate, sodium acetate, and sodiumchloride), disintegrating agents (e.g. starch, methyl cellulose, agar,bentonite, and xanthan gum), flavoring agents, and coloring agents mayalso be combined in the compositions or components thereof. Compositionsas described herein can further comprise wetting or emulsifying agents,or pH buffering agents.

A composition of the invention can be a liquid solution, suspension,emulsion, tablet, pill, capsule, sustained release formulation, orpowder. The compositions can be formulated as a suppository, withtraditional binders and carriers such as triglycerides. Oralformulations can include standard carriers such as pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, sodium saccharine,cellulose, magnesium carbonate, etc. Various delivery systems are knownand can be used to administer a composition of the invention, e.g.encapsulation in liposomes, microparticles, microcapsules, and the like.

Formulations for parenteral administration may include aqueoussolutions, syrups, aqueous or oil suspensions and emulsions with edibleoil such as cottonseed oil, coconut oil or peanut oil. Dispersing orsuspending agents dial can be used for aqueous suspensions includesynthetic or natural gums, such as tragacanth, alginate, acacia,dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, andpolyvinylpyrrolidone.

Compositions for parenteral administration may include sterile aqueousor non-aqueous solvents, such as water, isotonic saline, isotonicglucose solution, buffer solution, or other solvents conveniently usedfor parenteral administration of therapeutically active agents. Acomposition intended for parenteral administration may also includeconventional additives such as stabilizers, buffers, or preservatives,e.g. antioxidants such as methylhydroxybenzoate or similar additives.

Compositions of the invention can be formulated as pharmaceuticallyacceptable salts as described herein.

A composition of the invention may be sterilized by, for example,filtration through a bacteria retaining filter, addition of sterilizingagents to the composition, irradiation of the composition, or heatingthe composition. Alternatively, the compounds or compositions of thepresent invention may be provided as sterile solid preparations e.g.lyophilized powder, which are readily dissolved in sterile solventimmediately prior to use.

After pharmaceutical compositions have been prepared, they can be placedin an appropriate container and labeled for treatment of an indicatedcondition. For administration of a composition of the invention, suchlabeling would include amount, frequency, and method of administration.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of apharmaceutical composition of the invention to provide a beneficialeffect, in particular a sustained beneficial effect. Associated withsuch container(s) can be various written materials such as instructionsfor use, or a notice in the form prescribed by a governmental agencyregulating the labeling, manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use, or sale for human administration.

The invention also provides a kit comprising a compound or apharmaceutical composition of the invention. The kit can be a packagewhich houses a container which contains a composition of the inventionand also houses instructions for administering the composition to asubject.

Applications

The invention contemplates the use of compounds of the Formula I, II,III, IV, or V and compositions comprising the same for treating adisease disclosed herein, in particular preventing, and/or amelioratingdisease severity, disease symptoms, and/or periodicity of recurrence ofa disease disclosed herein. The invention also contemplates treating inmammals, diseases using the compounds, compositions or treatments of theinvention. The present invention in embodiments may provide acomposition comprising a compound that provides beneficial effectsincluding greater solubility, stability, efficacy, potency, and/orutility, in particular greater solubility and stability.

Novel compounds and methods for new therapeutic interventions are neededfor many areas of medicine and disease treatment. For example, chronicand acute inflammatory conditions form the basis for diseases affectingall organ systems including, but not limited to, asthma, acuteinflammatory diseases, vascular inflammatory disease, chronicinflammation, atherosclerosis, angiopathy, myocarditis, nephritis,Crohn's disease, arthritis, type I and II diabetes and associatedvascular pathologies. The incidence of these inflammatory conditions ison the rise and the expense is large. For example, for just one form ofinflammatory disease, Alzheimer's disease, the direct costs (such asmedications, doctors' fees, and nursing home care) and indirect costs(loss of productivity of those suffering Alzheimer's disease and loss ofproductivity of those caring for these individuals) are estimated toexceed one-hundred billion dollars per year.

With reference to the following examples and related discussions, thepresent invention provides various methods relating to the modulation ofinflammation, glial activation or phosphorylation pathways and/or newtherapeutic routes relating thereto. As illustrated more fully elsewhereherein, such methods include but are not limited to use of the compoundsand compositions of this invention, preferably in a dose dependentfashion, to selectively inhibit protein kinase activity, glialactivation response, oxidative stress-related responses such as nitricoxide synthase production and nitric oxide accumulation, cellularapoptosis and/or death associated protein kinase activity, and/orproinflammatory cytokine responses such as interleukin or tumor necrosisfactor production. Such methods can include the preparation and/orformulation of a composition with subsequent administration and/ordelivery to activated glial cells, tissue, culture or a relatedphysiological system or medium, such administration/delivery in a doseor at a compositional concentration sufficient to effect the desiredregulation and/or inhibition, without substantially inhibiting otherdesired endogenous anti-inflammatory responses.

In an aspect, the present invention relates to the inhibition ofneuronal cell death. Selective neuronal cell death is a characteristicfeature of the pathology of a number of neurodegenerative diseases,including Alzheimer's disease (AD), and traumatic brain injury, andstroke. Selected compounds and compositions of the present invention maybe used to reduce or inhibit Aβ-induced neuronal cell death and inparticular to reduce or inhibit calmodulin regulated protein kineses,such as death associated protein kinase (DAPK).

In some embodiments, the present invention provides methods ofinhibiting cell signaling molecule production (e.g., IL-1β and TNFα),comprising administering compositions comprising one or more of thecompounds of the Formula I, II, III, IV, or V, in particular one or morecompounds depicted in the Figures and Tables herein, in particular thecompounds depicted in Tables 2, 3, 4, or 5, or derivatives of thesecompounds.

The present invention also provides compounds (e.g., compounds listed inthe Figures and Tables for use in 1) lowering amounts of proinflammatorycytokines (e.g., TNFa or IL-1p) and/or 2) maintaining normal levels ofpostsynaptic proteins (e.g., PSD-95). In some embodiments, the reductionof pro-inflammatory cytokines reduces cytokines to levels found in anormal, healthy individual. In some embodiments, the compounds areprovided to an individual displaying characteristics of an inflammatorydisease (e.g., Alzheimer's disease), such that treatment with thecompounds reduces aberrantly high pro-inflammatory cytokine productioncaused by the disease (e.g., Aβ-induced increase in pro-inflammatorycytokines).

In another aspect, selected compounds and compositions of the inventionmay be used to modulate cytokine-mediated neuronal cell death, inparticular modulate cytokine-induced generation of NO, TNFα signalingthrough the Fas/TNFR family of death receptors, and/or DAPK, inAlzheimer's disease and other neurodegenerative disorders, and braininjury, and stroke. The evidence for the involvement of pro-inflammatorycytokines and NO in neuronal cell death has been reviewed in Akiyama,H., et al, (2000) Neurobiol. Agir g 21, 383-421; Prusiner, S. B. (2001)New Engl. J. Med. 344, 15 16-1526), cytokine-induced neuronal deathcould involve DAPK.

In part, the present invention also relates to the inhibition of celldeath or tissue loss and cell activation in addition to brain glia andneurons. For example, cell activation and tissue damage is acharacteristic of other diseases such as acute lung injury (ALI). ALIdue to sepsis, trauma or mechanical ventilation is associated with highmortality and morbidity, yet there are few effective therapies for thetreatment of ALL ALI is common during sepsis, which itself has an annualmortality equal to acute myocardial infarction. Endothelial cell (EC)dysfunction and activation has been implicated in the in vivo responseslinked to ALI, and EC protein kineses, such as myosin light chain kinase(MLCK), have been shown to be critical to EC barrier function andactivation. Similarly, the response of the heart to stress and acuteinjury results in acute and chronic injuries in which proteinphosphorylation regulated pathways and cell activation has been linkedto cell death and tissue damage. MLCK and related enzymes such as Rhokinase have been implicated in these processes and may be targets fornew therapeutics. Accordingly, compounds of the Formula I, II, III, IV,or V can be used to reduce injury from hypoxia-ischemia, acute lunginjury and/or endothelial cell dysfunction in lung or vascular tissue.

In another aspect of the invention, a method is provided for treating ina subject a disease involving or characterized by inflammation, inparticular neuroinflammation, comprising administering to the subject atherapeutically effective amount of a compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof. In afurther aspect, a method is provided for treating in a subject acondition involving inflammation, in particular neuroflammation,comprising administering to the subject a therapeutically effectiveamount of a composition comprising a compound of the Formula I, II, III,IV, or V and a pharmaceutically acceptable carrier, excipient, orvehicle.

In a further aspect, the invention provides a method involvingadministering to a subject a therapeutic compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of the Formula I, II, III, IV, or V,and a pharmaceutically acceptable carrier, excipient, or vehicle whichinhibit or reduce neuroflammation, activation of glia, proimflammatorycytokines, oxidative stress-related enzymes, acute phase proteins and/orcomponents of the complement cascade.

In another aspect, the invention provides a method for treating in asubject a disease associated with neuroinflammation that can bedecreased or inhibited with a compound disclosed herein comprisingadministering to the subject a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V, a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V and a pharmaceutically acceptable carrier,excipient, or vehicle.

In another aspect, the invention provides a method for preventing orinhibiting activation of protein kinases, in particular DAPK, in asubject comprising administering a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V a pharmaecuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V and a pharmaceutically acceptable carrier,excipient, or vehicle.

In a further aspect, the invention provides a method for reducing orinhibiting kinase activity, glial activation, neuronal cell damage,and/or neuronal cell death in a subject comprising administering to thesubject a therapeutically effective amount of a compound of the FormulaI, II, III, IV, or V a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of the Formula I, II, III, IV, or Vand a pharmaceutically acceptable carrier, excipient, or vehicle.

In some embodiments, the invention provides methods of inhibiting cellsignaling molecule production (e.g., IL-1β and TNFα), comprisingadministering compositions comprising one or more compounds of theFormula I, II, III, IV, or V, in particular the compounds depicted inthe Figures and Tables, more particularly Table 2, 3, 4 or 5, orderivatives of these compounds. In some embodiments, one or more of thecompounds, in particular the compounds depicted in the Figures andTables, more particularly Table 2, 3, 4 or 5 or derivatives of thesecompounds, are co-administered with other recognized therapeutics totreat inflammatory disease (e.g., neuroinflammatory disease, inparticular Alzheimer's disease). In some embodiments, the inventionprovides compounds (e.g., compounds listed in the Figures and Tables)for use in 1) lowering amounts of pro-inflammatory cytokines (e.g., TNFαor IL-1β) and/or 2) maintaining normal levels of postsynaptic proteins(e.g., PSD-95) for research, drug screening, or therapeutic purposes. Insome embodiments, the reduction of pro-inflammatory cytokines reducescytokines to levels found in a normal, healthy individual. In someembodiments, the compounds are provided to an individual displayingcharacteristics of an inflammatory disease (e.g., neuroinflammatorydisease, in particular Alzheimer's disease), such that treatment withthe compounds reduces aberrantly high pro-inflammatory cytokineproduction caused by the disease (e.g., Aβ-induced increase inpro-inflammatory cytokines).

In an aspect, the invention provides a method for amelioriatingprogression of a disease or obtaining a less severe stage of a diseasein a subject suffering from such disease (e.g., neuroinflammatorydisease, in particular a neurodegenerative disease, more particularlyAlzheimer's disease) comprising administering a therapeuticallyeffective amount of a compound of the Formula I, II, III, IV, or V, apharmaceutically acceptable salt thereof, or a composition comprising acompound of the Formula I, II, III, IV, or V and a pharmaceuticallyacceptable carrier, excipient, or vehicle.

The invention relates to a method of delaying the progression of adisease (e.g. neuroinflammatory disease, in particular aneurodegenerative disease, more particularly Alzheimer's disease)comprising administering a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V, a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V and a pharmaceutically acceptable carrier,excipient, or vehicle.

The invention also relates to a method of increasing survival of asubject suffering from a disease (e.g. neuroinflammatory disease, inparticular a neurodegenerative disease, more particularly Alzheimer'sdisease) comprising administering a therapeutically effective amount ofa compound of the Formula I, II, III, IV, or V, a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V and a pharmaceutically acceptable carrier,excipient, or vehicle.

The invention has particular applications in treating or preventing aneurodegenerative disease, in particular Alzheimer's disease. In anaspect of the invention a compound of the Formula I, II, III, IV, or Vis utilized in the treatment of Alzheimer's disease. Alzheimer's diseasemay be treated by administering a therapeutically effective amount of acompound of the Formula I, II, III, IV, or V. Such treatment may beeffective for retarding the degenerative effects of Alzheimer's disease,including specifically, but not exclusively, neuroinflammation,deterioration of the central nervous system, loss of mental facilities,loss of short term memory, and disorientation.

In another aspect, the invention provides a method for treatingAlzheimer's disease by providing a composition comprising a compound ofthe invention in an amount sufficient to reverse or inhibitneuroinflammation, activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity),neuronal cell damage, and/or neuronal cell death for a prolonged periodfollowing administration.

In a further aspect, the invention provides a method for treatingAlzheimer's disease in a patient in need thereof which includesadministering to the individual a composition that provides a compoundof the invention in a dose sufficient to reverse or inhibitneuroinflammation, activation of signaling pathways involved ininflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity),neuronal cell damage, and/or neuronal cell death for a prolonged periodfollowing administration.

The invention in an embodiment provides a method for treatingAlzheimer's disease, the method comprising administering to a mammal inneed thereof a composition comprising a compound of the invention in anamount sufficient to reduce cognitive decline for a prolonged periodfollowing administration, thereby treating the Alzheimer's disease.

In as aspect, the invention relates to a method of treatment comprisingadministering a therapeutically effective amount of one or more compoundof the Formula I, II, III, IV, or V, a pharmaceutically acceptable saltthereof, or a composition comprising a compound of the Formula I, II,III, IV, or V and a pharmaceutically acceptable carrier, excipient, orvehicle, which upon administration to a subject with symptoms of aneurodegenerative disease, in particular Alzheimer's disease, producesone or more therapeutic effect, in particular a beneficial effect, moreparticularly a sustained beneficial effect. In an embodiment, abeneficial effect is evidenced by a decrease or inhibition of one ormore of the following: inflammation (e.g. neuroinflammation), activationof signaling pathways involved in inflammation (e.g.,neuroinflammation), cell signaling molecule production, activation ofglia or glial activation pathways and responses, proinflammatorycytokines or chemokines (e.g., interleukin (IL) or tumor necrosis factor(TNF), oxidative stress-related responses such as nitric oxide synthaseproduction and nitric oxide accumulation, acute phase proteins,components of the complement cascade, protein kinase activity (e.g.,death associated protein kinase activity), cell damage (e.g., neuronalcell damage), and/or cell death (e.g., neuronal cell death).

In an embodiment, where the disease is Alzheimer's disease, beneficialeffects of a compound or composition or treatment of the invention canmanifest as one, two, three, four, five, six, seven, eight, or all ofthe following, in particular five or more, more particularly 7 or moreof the following:

-   a) A reduction in protein kinase activity (e.g. DAPK), in particular    at least about a 0.05%, 0.1%. 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%,    33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% decrease in    protein kinase activity.-   b) A reduction in glial activation response, in particular, at least    about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%,    40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% reduction in glial    activation.-   c) A reduction in glial activity in the brain, relative to the    levels determined in the absence of a compound of the Formula I, II,    III, IV, or V in subjects with symptoms of Alzheimer's disease. In    particular, the compounds induce at least about a 2%, 5%, 10%, 15%,    20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in glial activity-   d) A reduction in oxidative stress-related responses (e.g., nitric    oxide synthase production and/or nitric oxide accumulation), in    particular at least about a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%,    20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%    reduction in oxidative stress-related responses such as nitric oxide    synthase production and nitric oxide accumulation.-   e) A reduction in cellular apoptosis and/or death associated protein    kinase activity, in particular a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%,    15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or    99% reduction in cellular apoptosis and/or death associated protein    kinase activity.-   f) A reduction in proinflammatory cytokine responses in particular a    0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%,    45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% reduction in    proinflammatory cytokine responses.-   g) A reduction in interleukin-1β and/or tumor necrosis factorα    production in particular a 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%,    20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%    reduction in interleukin-1β and/or tumor necrosis factorα    production.-   h) A slowing of the rate of disease progression in a subject with    Alzheimer's disease.-   i) Increase in survival in a subject with symptoms of Alzheimer's    disease.

In particular aspects of the invention beneficial effects of compounds,compositions or treatments of the invention can manifest as (a) and (b);(a), (b) and (c); (a) through (d); (a) through (e); (a) through (f); (a)through (g); (a) through (h); or (a) through (i).

Compounds, pharmaceutical compositions and methods of the invention canbe selected that have sustained beneficial effects. In an embodiment, apharmaceutical composition with statistically significant sustainedbeneficial effects is provided comprising a therapeutically effectiveamount of a compound of the invention.

The invention provides a method for treating mild cognitive impairment(MCI) comprising administering a therapeutically effective amount of acompound of the formula I, II, III, IV, or V, a pharmaceuticallyacceptable salt thereof, or a composition comprising a compound of theFormula I, II, III, IV, or V and a pharmaceutically acceptable carrier,excipient, or vehicle.

In an embodiment, the invention provides a method of reversing orinhibiting neuroinflammation, activation of signaling pathways involvedin inflammation (e.g., neuroinflammation), cell signaling moleculeproduction, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines (e.g., interleukin(IL) or tumor necrosis factor (TNF), oxidative stress-related responsessuch as nitric oxide synthase production and nitric oxide accumulation,acute phase proteins, components of the complement cascade, proteinkinase activity (e.g., death associated protein kinase activity),neuronal cell damage, and/or neuronal cell death, after the onset ofcognitive deficits and Alzheimer's disease neuropathology in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of the Formula I, II, III, IV, or V, apharmaceutically acceptable salt thereof, or a composition comprising acompound of the Formula I, II, III, IV, or V and a pharmaceuticallyacceptable carrier, excipient, or vehicle.

The invention provides a method of preventing a disease disclosed hereinin a subject with a genetic predisposition to such disease byadministering an effective amount of a compound of the Formula I, II,III, IV, or V, or a pharmaceutically acceptable salt thereof, or acomposition comprising a compound of the Formula I, II, III, IV, or Vand a pharmaceutically acceptable carrier, excipient, or vehicle.

The invention provides a method of improving memory of a healthy subjector the memory of a subject with age impaired memory by administering aneffective amount of a compound of the Formula I, II, III, IV, or V, or apharmaceutically acceptable salt thereof, or a composition, comprising acompound of the Formula I, II, III, IV, or V and a pharmaceuticallyacceptable carrier, excipient, or vehicle.

The further provides a method for improving memory, especiallyshort-term memory and other mental dysfunction associated with the agingprocess comprising administering an effective amount of a compound ofthe Formula I, II, III, IV, or V, or a pharmaceutically acceptable saltthereof or a composition comprising a compound of the Formula I, II,III, IV, or V and a pharmaceutically acceptable carrier, excipient, orvehicle.

In an embodiment, a method is provided for treating a mammal in need ofimproved memory, wherein the mammal has no diagnosed disease, disorder,infirmity or ailment known to impair or otherwise diminish memory,comprising the step of administering to the mammal an effectivememory-improving amount of a compound of the Formula I, II, III, IV, orV, a pharmaceutically acceptable salt thereof, or a compositioncomprising a compound of the Formula I, II, III, IV, or V and apharmaceutically acceptable carrier, excipient, or vehicle.

In an aspect, the invention relates to a method of improving thelifespan of a subject suffering from Alzheimer's disease comprisingadministering a therapeutically effective amount of a compound of theFormula I, II, III, IV, or V, a pharmaceutically acceptable saltthereof, or a composition comprising a compound, of the Formula I, II,III, IV, or V and a pharmaceutically acceptable carrier, excipient, orvehicle.

In some aspects, greater efficacy and potency of a treatment of theinvention may improve the therapeutic ratio of treatment, reducinguntoward side effects and toxicity. Selected methods of the inventionmay also improve long-standing disease even when treatment is begun longafter the appearance of symptoms.

The compositions and methods described herein are indicated astherapeutic agents or methods either alone or in conjunction with othertherapeutic agents or other forms of treatment. They may be combined orformulated with one or more therapies or agents used to treat acondition described herein. Compositions of the invention may beadministered concurrently, separately, or sequentially with othertherapeutic agents or therapies. Therefore, the compounds of the FormulaI, II, III, IV, and/or V may be co-administered with one or moreadditional therapeutic agents including without limitationbeta-secretase inhibitors, alpha-secretase inhibitors, andepsilon-secretase inhibitors, agents that are used for the treatment ofcomplications resulting from or associated with a disease, or generalmedications that treat or prevent side effects.

The invention also contemplates the use of a composition comprising atleast one compound of the invention for the preparation of a medicamentin treating a disease disclosed herein. In an embodiment, the inventionrelates to the use of a therapeutically effective amount of at least onecompound of the invention for preparation of a medicament for providingtherapeutic effects, in particular beneficial effects, more particularlysustained beneficial effects, in treating a disorder or disease. In astill further embodiment the invention provides the use of a compound ofthe invention for the preparation of a medicament for prolonged orsustained treatment of a disease.

Administration

Compounds and compositions of the present invention can be administeredby any means that produce contact of the active agent(s) with theagent's sites of action in the body of a subject or patient to produce atherapeutic effect, in particular a beneficial effect, in particular asustained beneficial effect. The active ingredients can be administeredsimultaneously or sequentially and in any order at different points intime to provide the desired beneficial effects. A compound andcomposition of the invention can be formulated for sustained release,for delivery locally or systemically. It lies within the capability of askilled physician or veterinarian to select a form and route ofadministration that optimizes the effects of the compositions andtreatments of the present invention to provide therapeutic effects, inparticular beneficial effects, more particularly sustained beneficialeffects.

The compositions may be administered in oral dosage forms such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions, syrups, and emulsions. They may also be administered inintravenous (bolus or infusion), intraperitoneal, subcutaneous, orintramuscular forms, all utilizing dosage forms well known to those ofordinary skill in the pharmaceutical arts. The compositions of theinvention may be administered by intranasal route via topical use ofsuitable intranasal vehicles, or via a transdermal route, for exampleusing conventional transdermal skin patches. A dosage protocol foradministration using a transdermal delivery system may be continuousrather than intermittent throughout the dosage regimen. A sustainedrelease formulation can also be used for the therapeutic agents.

An amount of a therapeutic of the invention which will be effective inthe treatment of a particular disorder or disease to provide effects, inparticular beneficial effects, more particularly sustained beneficialeffects, will depend on the nature of the condition or disorder, and canbe determined by standard clinical techniques. The precise dose to beemployed in the formulation will also depend on the route ofadministration, and the seriousness of the disease, and should bedecided according to the judgement of the practitioner and eachpatient's circumstances.

Thus, the dosage regimen of the invention will vary depending upon knownfactors such as the pharmacodynamic characteristics of the agents andtheir mode and route of administration; the species, age, sex, health,medical condition, and weight of the patient, the nature and extent ofthe symptoms, the kind of concurrent treatment, the frequency oftreatment, the route of administration, the renal and hepatic functionof the patient, and the desired effect.

Suitable dosage ranges for administration are particularly selected toprovide therapeutic effects, in particular beneficial effects, moreparticularly sustained beneficial effects. A dosage range is generallyeffective for triggering the desired biological responses. The dosageranges are generally about 0.5 mg to about 2 g per kg, about 1 mg toabout 1 g per kg, about 1 mg to about 200 mg per kg, about 1 mg to about100 mg per kg, about 1 mg to about 50 mg per kg, about 10 mg to about100 mg per kg, or about 30 mg to 70 mg per kg of the weight of asubject.

A composition or treatment of the invention may comprise a unit dosageof at least one compound of the invention to provide beneficial effects.A “unit dosage” or “dosage unit” refers to a unitary i.e., a single dosewhich is capable of being administered to a patient, and which may bereadily handled and packed, remaining as a physically and chemicallystable unit dose comprising either the active agents as such or amixture with one or more solid or liquid pharmaceutical excipients,carriers, or vehicles.

A subject may be treated with a compound of the Formula I, II, III, IV,or V or composition or formulation thereof on substantially any desiredschedule. A composition of the invention may be administered one or moretimes per day, in particular 1 or 2 times per day, once per week, once amonth or continuously. However, a subject may be treated lessfrequently, such as every other day or once a week, or more frequently.A compound, composition or formulation of the invention may beadministered to a subject for about or at least about 1 week, 2 weeks to4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to6 months, 2 weeks to 12 months, 2 weeks to 18 months, or 2 weeks to 24months, periodically or continuously.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner.

EXAMPLES Example 1 General Materials and Methods

Synthetic Chemistry. All reagents and solvents were used as purchasedwithout further purification. Syntheses were done using variations ofestablished methods and in-parallel synthetic schemes. Briefly,diversification of position 3 of the pyridazine ring was done byreaction of a common halogenated pyridazine precursor. For the compoundsused in this report, a mixture of 0.01 mol of substitutedchloropyridazine, 0.05 mol of substituted piperazine and 0.01 mol ofammonium hydrochloride in 30 mL of 1-BuOH was stirred at 130° C. for 48h. The solvent was removed under reduced pressure. The residue was thenextracted with ethyl acetate, washed with water and brine, and driedover anhydrous NaiSO-i. Removal of solvent was followed byrecrystallization from 95% ethanol.

Animation of 3-chloro-6-phenylpyridazine by 2-(piperazin-1-yl)pyrimidine(FIG. 1 2) easily led to2-(4-(6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine (MW01-3-183WH):Light yellow crystals, yield. 96.4%; HPLC: 97.4% purity; HRMS calculated318.1587, found 318.1579; 1HNMR (CDCl3): 5 8.356 (d, J=4.5, 2H), 8.011(d, J=7.5, 11 2H), 7.692 (d, 3=9.5, 1H), 7.468 (t, 5 J=6.0, 2H), 7.417(d, J=7.5, 1H), 7.047 (d, J=9.5, 1H), 6.546 (t, J=4.5, 1H), 4.013 (t,J=5.0, 4H), 3.826 (t, J=5.0, 4H).

Reactions were monitored by analytical HPLC (Rainin Instruments SystemWoburn, Mass.), done on a reverse phase column CIS (25 cm×4.6 mm, 5 um,Supelco, Bellefonte, Pa.) with two different UV wavelengths (X=260 nmand X=220 nm or 300 nm). Eluents were (A): 0.1% (v/v) TFA in water and(B) 80% (v/v) acetonitrile/water containing 0.08% TFA. A linear gradientof 100/0 to 0/100 A/B over 34 min at 1 mL/min was used. 1H-NMR spectrawere obtained using Varian INOVA (500 MHz) spectrometer. High resolutionmass spectra were obtained on a VG70-250SE mass spectrometer.

Cell Culture Assays. BV-2 mouse microglial cells (5×103 cells/well in a48-well plate) were cultured and treated for 16 hrs with the standardglial activating stimulus lipopolysaccharide (LPS, from Salmonellatyphimurium; 100 ng/ml final concentration) in the presence or absenceof aminopyridazine compounds, as described previously [4, 17]. EL-1/3and TNFa levels in cell lysates were determined byelectro-chemiluminescent detection in a Meso-Scale Discovery (MSD) kit,as per the manufacturer's instructions.

In vivo Assays. Aβ-42 Infusions and treatment of C57B1/6 mice withMW01-2-151WH were performed as previously described [5]. Briefly,oligomeric A/31-42 was infused ICV for 28 days with a micro-osmoticpump. At post-operative day 21 and continuing for 14 days thereafter,mice were injected intraperitoneally once daily with either a testcompound (2.5 mg/kg per day) or solvent control (10% DMSO in saline). Atpost-operative day 60, mice were perfused and sacrificed, andhippocampal endpoints measured as previously described [5]. Endpointassays included immunohistochemical detection of activated astrocytesand microglia by glial fibrillary acidic protein (GFAP) and F4/80staining, measurement of the levels of the pro-inflammatory cytokinesIL-1|S, TNFa, and S100B by ELISA, and determination of synaptic damageby analysis of the levels of postsynaptic density protein-95 (PSD-95).

Brain Uptake Assays. MW01-2-151WH was administered to mice (25-30 g) byoral gavage using 2.5 mg/kg compound in 0.5% carboxymethylcellulosevehicle. At various times (0-60 min) after administration, mice weresacrificed, blood removed by cardiac puncture, and brains immediatelyharvested, weighed, quick-frozen in liquid nitrogen, and stored at −80°C. until assayed. Brain tissue was homogenized in 1.5 ml of 0.1 Mperchloric acid. After centrifugation (12,000×g for 10 min), thesupernatant was neutralized, with 1 M NaOH and then extracted threetimes with 2 ml of dichloromethane by centrifugation at 3,000×g for 5min. The organic phases from the three successive extractions werepooled and then vaporated to dryness under reduced pressure. The driedsample was reconstituted in 100 ul of HPLC mobile phase (80%acetonitrile, 0.08% formic acid, 20% H₂O), and 20 μl of thereconstituted material was injected into the HPLC system. The HPLCsystem for detection of MWO1-2-151WH was a Luna 5 μmCIS, 250 mm×2 mminternal diameter column together with a guard column (Phenomenex,Torrance, Calif., USA), with HPLC solvent delivered at 0.2 ml/min(Dionex, model P680 pump) and absorbance monitored at 282 run (Dionex,model UVD 170U detector). Under these experimental conditions, theretention time of the test compound was 15.3 min. A standard curve ofthe test compound was prepared by adding increasing concentrations ofthe compound to brain, tissue from untreated mice, then extracting thebrains and performing HPLC analysis as described above. The area underthe curve increased linearly with the concentration of the compound overthe range of concentrations investigated, with a correlation coefficientof 0.99. Under our experimental conditions, the compound was extractedreproducibly, with mean recoveries of 29 +/−2%.

Graded dose, acute toxicity assays Vehicle (30% DMSO) or test compound(3.1, 12.5 or 50 mg/kg) in 0.5% carboxymethylcellulose was administeredby oral gavage once dally for 3 days. On the 4th day, mice wereanesthetized with pentobarbital, intubated and the lungs were inflatedwith an aircontaining syringe. The mice were perfused through the rightventricle and the lungs, liver and kidneys were then harvested and fixedin 4% paraformaldehyde for histology. Paraffin embedded hematoxylin &eosin stained sections of each organ were prepared by standardtechniques. A pathologist blinded to the treatment groups performedmicroscopic assessment of the tissue for injury.

Results

MW01-3-183WH suppressed both IL-1β and TNFα production in aconcentration dependent manner (FIG. 2). As shown in FIG. 2 (parts A andB), concentration dependent inhibition of proinflammatory cytokineproduction by MW01-3-183WH in BV-2 cells were treated with LPS (100ng/ml) in the absence or presence of increasing concentrations ofMW01-3-183 WH for 16 hrs with levels of IL-1β and TNFα in cell lysatesmeasured by the Meso-Scale Discovery electrochemiluminescent detectionassay (See, Example 1., Materials and Methods). Data are the mean +/−SEM of triplicate determinations.

FIG. 3 illustrates that MW01-5-188WH is a concentration-dependent andselective inhibitor of proinflammatory cytokine production by activatedglia and does not cause liver injury after chronic oral administration.As shown in FIG. 3, concentration-dependent inhibition by MW01-5-188WHof LPS-induced increases in (A)IL-1β and (B) TNFα levels by the BV2microglial cell line. (C) Accumulation of the NO metabolite, nitrite,was not inhibited at concentrations up to 33 μM. MW01-5-188WH (188) doesnot suppress iNOS, COX-2 or apoE production in activated glia, asevidenced by the representative western blots for (D) iNOS, (E) COX-2and (F) apoE from glia cultures. Cultures were treated with controlbuffer, C, or activated in the absence, A, or presence, A+188, of 7.5μMW01-5-188WH. Daily oral administration of MW-01-5-188WH does not bringabout liver injury (G). Mice were administered either diluent orMW01-5-188 WH (2.5 mg/kg/day) for 2 weeks, then liver sections werestained with haematoxylin and eosin. Bar=125 μm. FIG. 4 illustrates thatoral administration of MW01-5-188WH suppresses human Aβ-inducedneuroinflammation in mouse hippocampus in the absence of a detectableeffect on the number of nitrotyrosine-labeled neurons, or on amyloidplaque deposition. Oral administration of MW01-5-188WH suppresses humanAβ-induced neuroinflammation in mouse hippocampus in the absence of adetectable effect on the number of nitrotyrosine-labeled neurons, or onamyloid plaque deposition. A schematic of the experimental paradigm isshown. Daily oral administration (2.5 mg/kg) of MW01-5-188WH(188-treated) for 2 weeks results in significant suppression of thehuman Aβ induced increase in (A) IL-1β, (B) TNFα and (C) S100B levels inhippocampal extracts (n=10 mice/group). MW01-5-188WH treatment alsodecreased the number of (D) GFAP-positive activated astrocytes and (E)F4/80 positive microglia in the hippocampus. (F) MW01-5-188WH treatment(188 treated) does not alter the profile of nitrotyrosine stainedneurons, an indicator of oxidative stress linked injury. Representativemicrographs are shown for hippocampus sections stained fornitrotyrosine-positive neurons, from vehicle-infused mice, Aβ-infusedmice (no treatment), and Aβ-infused mice orally administeredMW01-5-188WH (188-treated). Bars=25 μm. The number (G) of amyloidplaques or the area occupied by amyloid plaques (H) is not altered byMW01-5-188WH therapy. Quantification of amyloid burden from all mice(n=5/group) was done by determination of the amyloid load. Data are mean±SEM. Significantly different from Aβ-infused: *p<0.05, **p<0.01. FIG. 5illustrates that oral administration of MW01-5-188WH attenuateshippocampal synaptic dysfunction and hippocampus-linked behavioraldeficits. MW01-5-188WH administration significantly attenuated the lossof synaptophysin and PSD-95, and the behavioral deficit in the Ymaze.Oral administration of MW01-5-188WH attenuates hippocampal synapticdysfunction and hippocampus-linked behavioral deficits. A schematic ofthe experimental paradigm is shown in FIG. 5. MW01-5-188WHadministration significantly attenuated the loss of synaptophysin andPSD-95, and the behavioral deficit in the Ymaze. Levels of (A) thepre-synaptic protein synaptophysin and (B) the post-synaptic proteinPSD-95 were measured in hippocampal extracts from vehicle-infused mice(control), Aβ-infused mice (no treatment), and Aβ-infused miceadministered MW01-5-188WH (188-treated) at 2.5 mg/kg by oral gavage oncedaily for 2 weeks. (C) Spontaneous alternation of mice in the Y-maze, ahippocampus-dependent spatial learning task, was measured for 10 daysduring the 7th and 8th week after the start of Aβ infusion. Data aremean ±SEM of n=5 or 10 per group. Significantly different fromAβ-infused (*p<0.05, **p<0.01, ***p<0.001).

MW-01-2-151SRM was found to suppress IL-1β in a concentration dependentmanner. Immunoreactive levels of glial fibrillary acidic protein (GFAP),a marker of activated astrocytes were increased in Aβ-infused mice (Notreatment) compared to vehicle-infused mice (Control). The Aβ infusedincrease in GFAP levels was suppressed by administration ofMW01-2-151RSM. MW01-2-151RSM also blocked the Aβ-induced increase in thepro-inflammatory cytokines IL-1β, TNF-α, and S100B and the Aβ-inducedloss of the pre-synaptic protein, synaptophysin and post-synapticdensity protein PSD-95. These results are consistent with the results ofthe cell based assay. (See FIGS. 6 and 7.)

Example 2 Acute and Chronic Toxicity Assays

Liver toxicity is an especially important initial consideration fororally administered compounds, as the liver is the major site of initialdrug metabolism and is critical to overall metabolism and homeostasis ofan animal. Liver injury is also a component of idiopathic tissue injuryseen in certain chronically administered drugs. Therefore, it isimportant to do initial assessments of liver toxicity after oraladministration of compounds to mice.

Methods:

A standard approach is to test compounds in two initial in vivo toxicityassays: an acute, escalating-dose paradigm and a chronic, therapeuticdose regimen. For the escalating-dose, acute toxicity assays, mice (5per experimental group) are administered either compound or vehicle in0.5% carboxymethylcellulose (alternatively, castor oil or sesame oil canbe used) by oral gavage once daily for 3 days. Standard compound dosesare 3.1, 12.5, and 50 mg/kg; the highest dose is 20× a therapeutic dose.On the 4^(th) day, mice are sacrificed and the liver harvested and fixedfor histology. Paraffin-embedded, hematoxylin & eosin (H&E)-stainedsections of liver tissue are analyzed microscopically for injury by twoindividuals blinded to the treatment groups. A semi-quantitativehistological scoring system from 0 (best) to 9 (worst) is applied thatconsiders architecture features (normal to extensive fibrosis), cellularfeatures (normal to extensive edema and widespread necrosis), and degreeof inflammatory infiltrate (normal to extensive infiltrate). For eachacute toxicity assay, 15 mg of compound is required.

For the therapeutic dose, chronic toxicity assays, mice (5 perexperimental group) are administered either compound or vehicle in 0.5%carboxymethylcellulose by oral gavage once daily for 2 weeks at atherapeutic dose of 2.5 mg/kg/day. After two weeks of treatment, miceare sacrificed and liver toxicity analyzed as described above. For eachchronic toxicity assay, 5 mg of compound is required.

Results:

MW01-5-188WH has been tested in the acute, escalating-dose assay and thechronic, therapeutic dose assay. There was no histological evidence oftissue toxicity at the lower doses but some vacuolisation was observedat the 50 mg/kg dose.

MW01-2-151SRM has been tested in the chronic, therapeutic dose assay.There was no histological evidence of tissue toxicity; no differenceswere seen by histology in livers from mice treated with vehicle or withcompound. This compound is currently being tested in the acute,escalating dose assay.

MW01-6-189WH has been tested in the chronic, therapeutic dose assay.There was no histological evidence of tissue toxicity; no differenceswere seen by histology in livers from mice treated with vehicle or withcompound. This compound is being tested in the acute, escalating doseassay.

Example 3 hERG Channel Inhibition Assays and Cardiac QT Interval Assays

Compounds have been screened for hERG (human ether-a-go-go) potassiumion channel binding and inhibition in order to eliminate early in theprocess any compounds with high potential to induce prolongation ofcardiac QT interval in later studies due to off-target toxicities. ThehERG channel conducts rapidly activating delayed rectifier potassiumcurrents that critically contribute to cardiac repolarization. Mutationsin the hERG channel gene and drug-induced blockade of the currents havebeen linked to delayed repolarization of action potentials resulting inprolonged QT interval (Finlayson et al., 2004; Recanatini et al., 2005;Roden, 2004). QT prolongation is considered a significant risk factoragainst cardiac safety of new drugs. Therefore, consideration of cardiacsafety early in the development process by testing for hERG channelinhibition provides an efficient and predictive means to assesspotential compound cardiac safety liabilities. In addition, the FDA(USA) is considering this as an approval criteria in the future and hasspecific recommendations at this time. The assays done to date have beenby a commercial service (MDS PharmaService).

The initial assay is a radioligand binding assay that tests the abilityof the test compound to compete with ³H-astemizole (a reference standardthat binds to hERG channels with nM affinity) for binding to recombinanthERG channels stably expressed on human HEK-293 cells. This cell linewas chosen because it is of human origin, has been fully characterizedwith regard to hERG electrophysiology and pharmacology and displays theexpected characteristics of I_(Kr) current as well as expectedpharmacological sensitivities, and is easy to maintain in culture (Zhouet al., 1998). A single concentration (10 μM) of test compound isassayed, and % inhibition of ³H-astemizole binding is calculated.Generally, any compounds that show >50% inhibition are tested further inthe hERG channel activity assay. This is usual for medium throughoutscreens but is not recommended in the FDA document and tends to givefalse positives, as evidenced by the results reported below.

The hERG channel activity inhibition assay provides whole cellelectrophysiological data about compound effects on the hERG K⁺ channelfunction. Whole cell patch clamp methodology is generally considered tobe the gold-standard determination of ion channel activity, rather thansimply measuring channel binding. The standard testing procedure is touse 3 to 5 concentrations of compound at log dilutions with eachconcentration tested in triplicate (three cells). This allows a balancebetween achieving a reasonably accurate IC50 measurement against a broadconcentration range, and reducing cell attrition that would occur duringmore protracted experiment durations. After completion of compounddose-response procedures, a known hERG channel inhibitor, such asastemizole, is applied as a positive control.

Compounds which exhibit inhibition of hERG channel activity are verifiedas positives (the hERG channel activity assay can give false positivesand false negatives) by testing in vivo for prolongation of cardiac QTinterval. The QT interval studies are performed by evaluating compoundsfor effects on QT interval in Lead II electrocardiograms measured inanesthetized guinea pigs (Hirohashi et al., 1991), one of the speciesrecommended in the FDA white paper. Vehicle or compound is administeredorally at 15 mg/kg (dosing volume of 10 ml/kg) to groups of male guineapigs (weighing 330-350 g), with 5 animals per group. This dosecorresponds approximately to 20-fold the therapeutic dose by taking intoaccount the body surface area of the animals. Heart rate, arterial bloodpressure, and QT intervals are measured at baseline, and at 15, 30, 45,and 60 min after compound administration. Sotalol administered iv at 0.3mg/kg serves as the positive control compound. The QT intervals arecorrected for changes in heart rate using both Bazett's and Fridericia'sformulae. Any increase in QT interval values over baseline valuesexceeding the upper 95% confidence limit of the mean changes at thecorresponding time point in the vehicle-treated control group for twoconsecutive observation times indicates significant QT intervalprolongation in the individually treated animals. This functionaltesting in early discovery provides a rapid and cost-effective method tobetter anticipate and eliminate compounds that may have adverse QTprolongation potential in humans.

Calculations of Amount of Compound Needed:

-   Competition binding assay: 1-2 mg-   Patch clamp assay: 1-2 mg-   QT interval assay: 5 mg/animal/dose=25 mg per assay at 15 mg/kg dose

Because the ex vivo activity assays are subject to false positives andnegatives, it is considered better to complete studies of in vivo QTinterval assay following the guidelines of the PDA position paper.

Results: Competition Inhibition Assay:

MW01-5-188WH, MW01-2-151SRM, and MW01-6-127WH were tested at 10 μMconcentration.

MW01-5-188WH showed 91% inhibition at 10 μM. MW01-2-151SRM andMW01-6-127WH were negative, showing only 8% and 19% inhibition,respectively.

Patch Clamp Inhibition Assay:

MW01-2-151SRM and MW01-6-189WH were tested at three concentrations (0.1,1, 10 μM). These compounds showed minimal inhibition, with IC₅₀ valuesof 4.81 μM for MW01-6-189WH and 9.21 μM for MW01-2-151SRM.

Cardiac QT Interval Prolongation Assay:

MW01-5-188WH and MW01-2-151SRM were administered PO at 15 mg/kg to 5guinea pigs (330-350 g weight). QT intervals were obtained at baselineand at 15 min, 30 min, 45 min, and 60 min after compound administration.Neither compound increased cardiac QT interval above the mean +2 SD ofcorresponding values in the vehicle control group. There were also nosignificant effects on mean blood pressure or heart rate after compoundadministration.

Example 4 Preparation of2-(4-(6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine (MW01-3-183WH)

FIG. 1 depicts a synthetic scheme for the preparation of2-(4-(6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine (MW01-3-183WH).Reagent and condition: (a) 1-BuOH, NH4Cl, and 2-(piperazin-1-yl)pyrimidine. A typical reaction mixture of comprised about0.01 mol of 3-chloro-6-phenylpyridazine by 2-(piperazin-1-yl)pyrimidine,about 0.05 mol of 2-(piperazin-1-yl)pyrimidine and about 0.01 mol ofammonium hydrochloride was prepared in about 15 ml of 1-BuOH. Themixture was stirred at about 130° C. for about 48 h, and then thesolvent was removed under reduced pressure. The remaining residue wasthen extracted with ethyl acetate, washed with water and brine, driedover anhydrous Na₂SO₄. Removal of solvent followed by recrystallizationfrom 95% ethanol yielded light yellow crystals, yield 96.4%; HPLC: 97.4%purity: HRMS calculated 318.1587, found 318.1579; 1H NMR (CDCl3): δ8.356 (d, J=4.5, 2H), 8.011 (d, J=7.5, 11 2H), 7.692 (d, J=9.5, 1H),7.468 (t, J=6.0, 2H), 7.417 (d, J=7.5, 1H), 7.047 (d, J=9.5, 1H), 6.546(t, J=4.5, 1H), 4.013 (t, J=5.0, 4H), 3.826 (t, J=5.0, 4H).

Example 5 Biological Activity, Metabolic Stability and Toxicity of4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(W01-2-151SRM)

As shown in FIG. 6 (parts A-D) and FIG. 7 parts A-G), the biologicalactivity of MW011-2-151SRM was investigated using the assays describedherein for biological activity of the compounds. The compound was orallyavailable, and targeted to glia responses to protect againstneurodeneration, but did not suppress the same inflammatory responseendpoints outside the brain. The compound was a selective suppressor ofactivated glia responses, especially key proinflammatory responses thathave been linked to AD pathology. It also showed efficacy in the mousemodel of human Aβ-induced neuroinflammation and neuronal injury as shownby the assays of FIG. 7 (parts A-G).

The stability of MW01-2-151SRM in microsomes, as shown in FIGS. 47 and48, was demonstrated for MW01-2-151SRM. The stability of MW01-5-188WH (1μM) in a standard incubation with rat liver microsomes (BD Biosciences)and an NADPH-regenerating system was done at 37° C. for the times shown.Reactions were stopped by acetonitrile, and the reaction mixture wascentrifuged at 16 000×g for 10 min, 10 μl of the supernatant wasanalyzed by calibrated HPLC to quantify the percentage of the initialamount of MW01-2-151SRM remaining after the incubation. The HPLC system(Dionex Corp., Sunnyvale, Calif.) includes a Dionex P480 pump, aPhenomenex Luna. (318 column (250×2.0 mm, 5□m) with a guard column(Phenomenex, Torrance, Calif.) and a Dionex UVD340U Ultraviolet (UV)detector. The mobile phase consisted of 0.1% formic acid as reagent Aand 0.08% formic acid/water in 80% acetonitrile as reagent B, at a flowrate of 0.2 ml per minute. The gradient consisted of the followinglinear and isocratic gradient elution changes in reagent B: isocratic at60% from 0 to 5 min, 60% to 90% from 5 to 39 min, isocratic at 90% until44 min. Peak quantification was done based on absorption measured at 260nm relative to a standard curve obtained by using serial dilutions ofMW01-2-151SRM.

Liver toxicity after chronic in vivo administration of MW01-2-151SRM wasinvestigated, see FIG. 47 A. Mice were administered by oral gavageeither MW01-2-151 SRM (2.5 mg/kg/day) or diluent (10% DMSO) in a 0.5%(w/v) carboxymethylcellulose suspension once dally for two weeks. Micewere anesthetized and sacrificed. Livers were removed, fixed in 4% (v/v)paraformaldehyde and paraffin-embedded for histology. To assesshistological toxicity, 4 □m liver sections were stained withhaematoxylin and eosin. Two independent observers blinded to thetreatment groups performed microscopic assessment of the tissue forinjury.

Example 6 Preparation ofN-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW1-7-084WH)

A synthetic scheme for the preparation ofN-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4- yl)pyridazin-3-amine(MW01-7-084WH) is depicted in FIG. 8, and synthesis was carried out asdescribed herein.

4-chloro-6-phenylpyridazin-3(2H)-one (MW01-6-093WH)

4-chloro-6-phenylpyridazin-3(2H)-one was synthesized according to theprocedure described by Coudert, P. [18].

4-chloro-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (MW01-7-053WH)

A mixture of chloropyridazinone 1 (25.5 g, 0.12 mol),4-N,N-dimethylaminopyridine (0.20 g) and i-Pr2NEt (26.7 g, 0.21 mol) inanhydrous CH₂Cl₂ (300 mL) was stirred at 0° C. (ice bath) for 30 min.Methoxymethyl chloride (25 g, 0.31 mol) was added and the mixture wasstirred at 0 _(i)ãC for 1 h and then allowed to warm to roomtemperature. The reaction was stirred at room temperature till complete.The solvent was then removed in vacuo, the residue was treated withwater, washed with dilute Na₂CO₃ solution and extracted with EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and evaporated.The residue was then purified by re-crystallization from 95% ethanol togive 20.1 light yellow solid. Yield 66.9%.

6-phenyl-4-(pyridin-4-yl)pyridazin-3(2H)-one (MW01-7-069WH)

The protected pyridazinone MW01-7-053WH (1.0 equiv.) was mixed witharylboronic acid (1.37 equiv.), Pd(PPh3)4 (0.05 equiv.) and K2CO3 (3.1equiv) and 200 mL of DME in a 350 ml of pressure vessel, flushed withargon for 3 min, and the mixture was then stirred and refluxed (oilbath, 120° C.) until the starting material had disappeared. Aftercooling, the solution was concentrated to dryness under reducedpressure, the residue was treated with water and filtered off. Thefilter cake was washed with water over filter funnel and then used fornext step directly. The residue obtained above was dissolved in 200 mlof EtOH, 6 N HCl (200 mL) was added and the reaction mixture wasrefluxed (oil bath, 12.0 _(i)ãC) for 6 h, then it was allowed to cool toroom temperature, and concentrated to dryness under reduced pressure.The residue was neutralized with dilute NaOH solution. The suspensionwas then filter off, washed with water and dried over filter funnel.Recrystallization from 90% ethanol provided brown yellow solid. Yield80.4%. ESI-MS: m/z 294.3 (M+H+)

3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH)

3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH) (66 mmol)was suspended in 75 ml phosphorus oxychloride and heated with stirringat 100° C. for 3 h. After cooling to room temperature the mixture waspoured onto crushed ice. The mixture was then neutralized with NaOHsolution to give white suspension. The precipitation was filtered off,washed with water, dried over filter funnel to yielding a light yellowsolid. ESI-MS: m/z 268.4 (M+H+).

N-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-084WH)

A mixture ofN-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-084WH) (0.5 mmol), C-Cyclopropyl-methylamine (2.0 mmol) in 3 mlof 1-BuOH was heated with stirring at 130° C. for 7 days. The solventwas removed by evaporation in vacuo, the residue was treated with waterto give a suspension. The solid was then filtered off, washed withwater, then 1:3, Ethyl Acetate: Petroleum ether, dried over filterfunnel in vacuo yielding gray solid. ESI-MS: m/z 330.4 (M+H+).

Example 7 Preparation of3-(4-methylpiperazin-1-yl)-6-phenyl-4-(pyridin-4-yl)pyridazine(MW01-7-085WH).

A mixture of 3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH)(0.5 mmol), 1-methyl-piperazine (2.0 mmol) in 3 ml of 1-BuOH was heatedwith stirring at 130° C. for about 7 days. The solvent was removed byevaporation in vacuo, the residue was treated with water to give asuspension. The solid was then filtered off, washed with water, then1:3, Ethyl Acetate: Petroleum ether, dried over filter funnel in vacuoto yield a brown solid. ESI-MS: m/z 332.2 (M+H+). A synthetic reactionscheme for the preparation of3-(4-methylpiperazin-1-yl)-6-phenyl-4-(pyridin-4-yl)pyridazine(MW01-7-085WH) is depicted in FIG. 9.

Example 8 Preparation ofN-(2-morpholinoethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-091WH).

A mixture of 3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH)(0.5 mmol), 2-Morpholin-4-yl-ethylamine (2.0 mmol) in 3 ml of 1-BuOH washeated with stirring at 130° C. for about 7 days. The solvent wasremoved by evaporation in vacuo, the residue was treated with water togive a suspension. The solid was then filtered off, washed with water,then 1:3, Ethyl Acetate: Petroleum, ether, dried over filter funnel invacuo to yield a gray solid. ESI-MS: m/z 362.2 (M+H¹). A syntheticreaction scheme for the preparation of3-(4-methylpiperazin-1-yl)-N-(2-morpholinoethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-091WH) is depicted in FIG. 10.

Example 9 Preparation of5-(4-Fluorophenyl)-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-065LKM).

A synthetic reaction scheme for the preparation of5-(4-Florophenyl)-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-065LKM) is depicted in FIG. 11, and synthesis was carried out asdescribed herein.

3-phenyl-6-(4-pyrimidin-2-piperazin-1-yl)pyridazin-5-ol (MW01-6-006WH)

This compound was prepared from 3-chloro-5-hydroxy-6-phenylpyridazine(1.4 g, 6.8 mmol) in the same manner as described for MW01-6-121WH,yielding white solid (2.12 g, 6.15 mmol, 90.4%). MALDI-TOF: m/z 335.7(M+H+). 1H NMR (DMSO): d 8.433 (t, J=2.0, J=2.4, 2H), 7.773 (d, J=3.2,2H), 7.497 (t, J=2.0, J=3.6, 3H), 7.182 (s, 1H), 6.727 (s, 1H), 3.949(s, 4H).

5-chloro-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-015WH)

3-chloro-5-hydroxy-6-phenylpyridazine (66 mmol) was suspended in 75 mlphosphorus oxychloride and heated with stirring at 100° C. for 3 h.After cooling to room temperature the mixture was poured onto crushedice. The mixture was then neutralized with NaOH solution to give whitesuspension. The precipitation was filtered off, washed with water, driedover filter funnel to yield white solid (98.8%). ESI-MS: m/z 353.3(M+H+). 1H NMR (CDCl3): d 8.375 (d, J=5.0, 2H), 7.776 (d, J=7.0, 2H),7.487 (m, 3H), 7.073 (s, 1H), 6.588 (t, J=4.5, 1H), 4.046 (t, J=4.5,J=5.5, 4H), 3.849 (t, J=5.5, J=5.0, 4H).

5-(4-Florophenyl)-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-065LKM)

This compound was prepared in the same manner as described forMW01-7-069WHWH, yielding a white solid (60.4%). MALDI-TOF: m/z 413.4(M+H+).

Example 10 Preparation of5-(4-pyridyl)-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-069A-SRM)

A synthetic reaction scheme for the preparation of5-(4-pyridyl)-3-phenyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-069A-SRM) is depicted in FIG. 12, and synthesis was carried outas described herein. This compound was prepared in the same manner asdescribed for MW01-2-065LKM, yielding white solid (65.4%). MALDI-TOF:m/z 396.2 (M+H+).

Example 11 Preparation of4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-151SRM).

4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-151SRM) was prepared by several synthetic schemes as depicted inFIG. 13 (Scheme 1), FIG. 14 (Scheme 2), and FIG. 15 (Scheme 3), whichwere carried out as described in detail herein. The various reactionschemes (Schemes 1, 2, and 3) are generally applicable to the compoundsof the present invention and are not restricted in utility only to thepreparation of MW01-2-151SRM.

Scheme 1

3-chloro-6-phenylpyridazin-4-ol was synthesized according to theprocedure described by Coudert, P., et al. [18].

6-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazin-4-ol(MW01-7-121WH)

This compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine(14 g, 68 mmol) in the same manner as described below, yielding whitesolid (22.1 g, 66 mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR (DMSO):1H NMR (DMSO): d 8.406 (d, J=6.5, 2H), 7.740 (d, J=4.0, 2H), 7.558 (s,3H), 6.686 (t, J=4.8, J=4.4, 1H), 6.841 (s, 1H), 3.881 (s, 4H), 3.620(s, 4H), 3.776 (s, 4H).

4-chloro-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-127WH)

6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66mmol) was suspended in 75 ml phosphorus oxychloride and heated withstirring at 100° C. for 3 h. After cooling to room temperature themixture was poured onto crushed ice. The mixture was then neutralizedwith NaOH solution to give white suspension. The precipitation wasfiltered off, washed with water, dried over filter funnel to providewhite solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR(CDCl3): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H),7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672(t, J=4.0, J═4.5, 4H).

4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-2-151SRM)

Into a reaction tube were added MW01-6-127WH (1.4 g, 4.0 mmol), K2CO3powder (1.7 g, 12.4 mmol), Pd(dppf)Cl2 (326 mg, 0.4 mmol), silver oxide(2.3 g, 10 mmol), methylboronic acid (324 mg, 5.4 mmol) and 20 ml ofTHF. Argon was then flushed through the tube for 3 min. The tube wasthen sealed tightly and heated with stirring at 80 degree for 12 h.After cooled down, the mixture was quenched with 10% NaOH solution andextracted with ethyl acetate. The organic phase was concentrated invacuo and the residue was purified by column chromatography eluting with1:4, Ethyl Acetate: Petroleum ether. White powder solid was obtained(0.60 g, 1.8 mmol, yield 45.2%). ESI-MS: m/z 333.4 (M+H+). 1H NMR(CDCl3): d 8.380 (d, J=5.0, 2H), 7.065 (d, J=7.0, 2H), 7.626 (s, 1H),7.473 (m, 3H), 6.567 (t, J=4.5, J=5.0, 1H), 4.056 (t, J=5.0, 4H), 3.475(t, J=5.0, 4H), 2.456 (s, 3H).

Scheme 2

Into a reaction tube were added MW01-6-127WH (1.4 g, 4.0 mmol), K2CO3powder (1.7 g, 12.4 mmol), Pd(PPh₃)₄ (240 mg, 0.2 mmol), silver oxide(2.3 g, 10 mmol), methylboronic acid (324 mg, 5.4 mmol) and 20 ml ofDME. Argon was then flushed through the tube for 3 min. The tube wasthen sealed tightly and heated with stirring at 120° C. for 24 h. Aftercooled down, the mixture was filter through acelite earth, the filtratewas then concentrated and the residue was purified by columnchromatography during with 1:4, Ethyl Acetate:Petroleum ether. Whitepowder solid was obtained (0.64 g, 1.93 mmol, yield 48.1%). ESI-MS: m/z333.4 (M+H+). 1H NMR (CDCl3): d 8.380 (d, J=5.0, 2H), 7.065 (d, J=7.0,2H), 7.626 (s, 1H), 7.473 (m, 3H), 6.567 (t, J=4.5, J=5.0, 1H), 4.056(t, J=5.0, 4H), 3.475 (t, J=5.0, 4H), 2.456 (s, 3H).

Scheme 3

4,5-dihydro-4-methyl-6-phenylpyridazin-3(2H)-one (MW01-8-004WH)

7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid was added to a100 ml single-necked round bottom flask followed by 3.0 ml (60 mmole) ofhydrazine monohydrate and then 20 ml of reagent grade ethanol (100%, 95%of ethanol should be fine also). The flask was fitted with a refluxcondenser and the reaction mixture was heated to reflux in an oil bathat 110 C (temperature of oil bath) and stirred for 2 h. The flask wasthen removed from the oil bath and the reaction mixture cooled toambient temperature. The stir bar was removed and the solvent wasevaporated in vacuo in a water bath at 45° C. The residue was thentreated with 50 ml of Milli-Q water and stirred, for 10 minutes to givea suspension. The precipitate was collected by filtering, washed with100 ml of 2N NaHCO₃, then washed with 60 ml Milli-Q water three times,and dried over a medium frit sintered glass funnel in vacuo to give 7.15g of white crystals (Syn. ID, WH-8-004). Yield, 95%, confirmed byESI-MS. ESI-MS: m/z 189.2 (M+H+).

4-methyl-6-phenylpyridazine-3(2H)-one (MW01-8-008WH)

7.0 g (35 mmole) of MW01-8-004WH was placed in a 100 ml single-neckedround bottom flask followed by 9.4 g (70 mmole) of anhydrous copper (II)chloride and then 30 ml of acetonitrile to give a brown yellowsuspension. A reflux condenser was connected to the flask and a dry tubefilled with CaCl2 was fitted to the top of the condenser. The reactionmixture was heated to reflux in an oil bath (110° C.) for 3 h. The colorof the reaction suspension changed to dark yellow once the refluxstarted. After the completion of the reaction (monitored by HPLC), theflask was removed from the oil bath and cooled to ambient temperature.The mixture was poured on to 300 g of crushed ice and stirred vigorouslyfor 10 minutes to give a gray precipitate and blue liquid. Theprecipitate was then collected by filtering (pH of the filtrate was1.5-2.0), and washed with 100 ml of a 1N HCl solution to rid the solidof any remaining copper byproducts. This is followed by washing with 100ml of Milli-Q water to get rid of the acid in the solid, and ismonitored by checking the pH value of the filtrate. The solid was washeduntil the filtrate shows a pH of 7, after approximately 5 washes. Thesolid was dried over a medium frit sintered glass funnel in vacuo togive 6.3 g of a blue gray solid. Yield was 96.7% and confirmed byESI-MS. ESI-MS: m/z 187.3 (M+H+).

3-chloro-4-methyl-6-phenylpyridazine (MW01-8-012WH)

6.0 g (32 mmole) of MW01-8-008WH and 30 ml (320 mmole) of phosphorusoxychloride were placed in a 100 ml single-necked round bottom flask.The flask was connected with a reflux condenser and a dry tube filledwith anhydrous CaCl₂ was fitted to the top of the condenser. (HCl gas isformed in the reaction so a basic solution such as NaOH may be needed toabsorb HCl in a large-scale synthesis). The reaction mixture was stirredin an oil bath (90° C.) for 2 h, then cooled to ambient temperature andpoured onto crushed ice. (phosphorus oxychloride can be decomposed bywater to give HCl and H₃PO₄). The mixture was then stirred vigorouslyfor 10 minutes to give a white suspension. The suspension wasneutralized with a 2N NaOH solution until the pH of the suspension waspH=7. The precipitate was filtered, washed three times with 100 ml ofMilli-Q water and dried over a medium frit sintered glass funnel invacuo to provide 5.9 g of a light pink powder (Syn. ID, WH-8-012). Yieldwas 89.4% and confirmed by ESI-MS. ESI-MS: m/z 205.4 (M+H+).

2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-2-151SRM)

0.82 g (4.0 mmole) of WH-8-012 was placed in a 30 ml pressure vesselfollowed by addition of 2.6 g (16.0 mmole) of 1-(2-pyrimidyl)piperazineand then 15 ml of 1-BuOH. The vessel was sealed tightly and placed intoan oil bath, and stirred at 130 C (temperature of oil bath) for 2.5days. The reaction mixture was then cooled to ambient temperature andtransferred to a single-necked flask for evaporation under reducedpressure. Removal of solvent gave rise to a brown-red residue that wastreated with 30 ml of water to give a brown sticky oil. The mixture waskept at ambient temperature overnight while the oil solidifiedgradually. The formed solid was then broken into small pieces with asteel spatula. The solid was collected by filtering and washed with 50ml of Milli-Q water three times and dried over a filter funnel in vacuoto provide 1.25 g of light yellow solid (Syn. ID, WH-8-020). Yield was94%. (Alternative separation is to use precipitation procedure insteadof solidification process. Solidification is a simple and cheapoperation, yet time-consuming. Precipitation is time efficient, yet morecostly than the former one. So it is up to the process chemist to decidewhich procedure to pick for the manufacture. The precipitation processis below: The oil product was dissolved completely in 10 ml of reagentgrade ethanol or acetone to form a solution. The solution was then addeddropwise to 150 ml of ice water under vigorous stirring. Light yellowsuspension was then formed gradually. The solid was collected byfiltering, washed with Milli-Q water, dried over filter funnel in vacuoto give the desired product.) The final compound was confirmed by ESI-MSand NMR. ESI-MS: m/z 333.8 (M+H+). 1H NMR (CDCl3): d 8.380 (d, J=5.0,2H), 7.065 (d, J=7.0, 2H), 7.626 (s, 1H), 7.473 (m, 3H), 6.567 (t,J=4.5, J=5.0, 1H), 4.056 (t, J=5.0, 4H), 3.475 (t J=5.0, 4H), 2.456 (s,3H).

Example 12 Preparation of4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-5-188WH).

4.6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-5-188WH)was prepared by several synthetic schemes as depicted in FIG. 16 (Scheme1), FIG. 17 (Scheme 2), and FIG. 18 (Scheme 3), which were carried outas described in detail herein. The various reaction schemes (Schemes 1,2, and 3) are generally applicable to the compounds of the presentinvention and are not restricted in utility only to the preparation ofMW01-2-188WH.

Scheme 1

3-chloro-6-phenylpyridazin-4-ol was synthesized according to theprocedure described by Coudert, P., et al. [18],

6-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazin-4-ol(MW01-7-121WH)

The compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14g, 68 mmol). A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOHwas heated with stirring at 130° C. for 3 days. The solvent was removedby evaporation in vacuo, the residue was treated with water to give asuspension. The solid was then filtered off, washed with water, driedover filter funnel in vacuo to give light pink solid, yielding whitesolid (22.1 g, 66 mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR (DMSO):1H NMR (DMSO): d 8.406 (d, J=6.5, 2H), 7.740 (d, J=4.0, 2H), 7.558 (s,3H), 6.686 (t, J=4.8, J=4.4, 1H), 6.841 (s, 1H), 3.881 (s, 4H), 3.620(s, 4H), 3.776 (s, 4H).

4-chloro-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-127WH)

6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66mmol) was suspended in 75 ml phosphorus oxychloride and heated withstirring at 100° C. for 3 h. After cooling to room temperature themixture was poured onto crushed ice. The mixture was then neutralizedwith NaOH solution to give white suspension. The precipitation wasfiltered off, washed with water, dried over filter funnel to providewhite solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR(CDCl3): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H),7.508 (m, 3H), 6.564 (1, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672(t, J=4.0, J=4.5, 4H).

4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-5-188WH)

A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol),1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH washeated with stirring at 130° C. for 3 days. The solvent was removed byevaporation in vacuo, the residue was treated with water to give asuspension. The solid was then filtered off washed with water, driedover filter funnel in vacuo to give light pink solid. (320 mg, 0.81mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979, found395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H),7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, J=4.5,1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5. 4H).

Scheme 2

4,5-dihydro-6-phenyl-4-phenylpyridazin-3(2H)-one

135 ml (135 mmole) of a solution of phenylmagnesium bromide (1M) in THFwas added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, leftovernight at ambient temperature, then decomposed with a saturatedsolution of ammonium chloride. The organic layer was separated, and theaqueous layer was extracted with 100 ml of ethyl acetate. The solventwas removed and the residue was crystallized from ethanol. The crystalswere collected by filtering and dried over a medium frit sintered glassfunnel in vacuo to give 5.6 g of white crystals. Yield was 50%,confirmed by ESI-MS, ESI-MS: m/z 250.1 (M+H+).

6-phenyl-4-phenylpyridazin-3(2H)-one

4.4 g (17.5 mmole) of 6-pyridazinone obtained above was placed in a 50ml single-necked round bottom flask followed by 4.7 g (35 mmole) ofanhydrous copper (II) chloride and then 20 ml of acetonitrile to give abrown yellow suspension. A reflux condenser was connected to the flaskand a dry tube filled with CaCl2 was fitted to the top of the condenser.The reaction mixture was heated to reflux in an oil bath (110 C) for 3h. The color of the reaction suspension changed to dark yellow once thereflux started. After the completion of the reaction (monitored byHPLC), the flask was removed from the oil bath and cooled to ambienttemperature. The mixture was poured on to 200 g of crushed ice andstirred vigorously for 10 minutes to give a gray precipitate and blueliquid. The precipitate was then collected by filtering (pH of thefiltrate was 1.5-2.0), and washed with 50 ml of a 1N HCl solution to ridthe solid of any remaining copper byproducts. This is followed bywashing with 100 ml of Milli-Q water to get rid of the acid in thesolid, and is monitored by checking the pH value of the filtrate. Thesolid was washed until the filtrate shows a pH of 7, after approximately5 washes. The solid was dried over a medium frit sintered glass funnelin vacuo to give 3.9 g of a blue gray solid. Yield was 90%, confirmed byESI-MS. ESI-MS: m/z 248.1 (M+H+).

3-chloro-6-phenyl-4-phenylpyridazine

2.0 g (8 mmole) of 6-phenylpyridazinone obtained above and 10 ml (54mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed ina 50 ml single-necked round bottom flask. The flask was connected with areflux condenser and a dry tube filled with CaCl2 was fitted to the topof the condenser. (HCl gas is formed in the reaction so a basic solutionsuch as NaOH may be needed to absorb HCl in a large-scale synthesis).The reaction mixture was stirred in an oil bath (90 C) for 2 h, thencooled to ambient temperature and poured onto crushed ice. (phosphorusoxychloride can be decomposed by water to give HCl and H3PO4). Themixture was then stirred vigorously for 10 minutes to give a whitesuspension. The suspension was neutralized with a 2N NaOH solution untilthe pH of the suspension was pH=7. The precipitate was filtered, washedthree times with 100 ml of water and dried over a medium frit sinteredglass funnel in vacuo to provide 1.8 g of a light pink powder. Yield was85%, confirmed by ESI-MS. ESI-MS: m/z 266.4 (M+H+).

2-(4-(6-phenyl-4-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine

1.1 g (4.0 mmole) of 3-chloropyridazine obtained above was placed in a30 ml pressure vessel followed by addition of 2.6 g (16.0 mmole) of1-(2-pyrimidyl)piperazine and then 15 ml of 1-BuOH (reagent grade). Thevessel was sealed tightly and placed into an oil bath and stirred at130° C. (temperature of oil bath) for 3 days. The reaction mixture wasthen cooled to ambient temperature and transferred to a single-neckedflask for evaporation under reduced pressure. Removal of solvent gaverise to a brown-red residue that was treated with 30 ml of water to givea brown suspension. The solid was collected by filtering and washed with50 mL of water three times and dried over a filter funnel in vacuo toprovide 0.96 g of light yellow solid. Yield was 90%, ESI-MS: m/z 395.5(M+H+). HRMS calcd 395.1979, found 395.1973; 1H NMR (CDCl3): d 8.329 (d,J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1H),7.509 (m, 6H), 6.530 (t, J=4.5, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394(t, J=5.0, J=4.5, 4H).

Scheme 3

3-chloro-6-phenylpyridazin-4-ol was synthesized according to theprocedure described by Coudert, P., et al. [18].

4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-5-188WH)

A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol),1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH washeated with stirring at 130 C for 3 days. The solvent was removed byevaporation in vacuo, the residue was treated with water to give asuspension. The solid was then filtered off, washed with water, driedover filter funnel in vacuo to give light pink solid. (320 mg, 0.81mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979, found395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H),7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, J=4.5,1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H).

Example 13 Preparation of4-pyridyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-189WH).

4-pyridyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-189WH) was prepared by two synthetic schemes as depicted in FIG.19 (parts (A) and (B)), which were carried out as described in detailherein. The various reaction schemes (Schemes 1 and 2) are generallyapplicable to the compounds of the present invention and are notrestricted in utility only to the preparation of MW01-2-189WH.

Scheme 1

3-chloro-6-phenylpyridazin-4-ol was synthesized according to theprocedure described by Coudert, P., et al. [18].

6-phenyl-3-(4-pyrimidin-2-yl)piperazin-1-yl)pyridazin-4-ol(MW01-7-121WH)

This compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine(14 g, 68 mmol) A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg,1.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of1-BuOH was heated with stirring at 130° C. for 3 days. The solvent wasremoved by evaporation in vacuo, the residue was treated with water togive a suspension. The solid was then filtered off, washed with water,dried over filter funnel in vacuo to give light pink solid. yieldingwhite solid (22.1 g, 66 mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR(DMSO): 1H NMR (DMSO): d 8.406 (d, J=6.5, 2H), 7.740 (d, J=4.0, 2H),7.558 (s, 3H), 6.686 (t, J=4.8, J=4.4, 1H), 6.841 (s, 1H), 3.881 (s,4H), 3.620 (s, 4H), 3.776 (s, 4H).

4-chloro-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-5-127WH)

6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol 1h (22.0 g, 66mmol) was suspended in 75 ml phosphorus oxychloride and heated withstirring at 100 for 3 h. After cooling to room temperature the mixturewas poured onto crushed ice. The mixture was then neutralized with NaOHsolution to give white suspension. The precipitation was filtered off,washed with water, dried over filter funnel to provide white solid (21.3g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR. (CDCl3): d 8.377(d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H),6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672 (t, J=4.0,J=4.5, 4H).

4-pyridyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-189WH)

Into a reaction tube were added WH-6-127 (1.4 g, 4.0 mmol), K2CO3 powder(1.7 g, 12.4 mmol), Pd(PPh3)4 (240 mg, 0.2 mmol), 4-pyridineboronic acid(664 mg, 5.4 mmol) and 20 ml of DME. Argon was then flushed through thetube for 3 min. The tube was then sealed tightly and heated withstirring at 120 degree for 24 h. After cooled down, the mixture wasfilter through a celite earth, the filtrate was then concentrated andthe residue was purified by column chromatography eluting with 1:4,Ethyl Acetate:Petroleum ether. Tight yellow needle crystals wereobtained (0.65 g, 1.65 mmol, yield 41.2%). Confirmed by ESI-MS and NMR.ESI-MS: m/z 396.2 (M+H+). 1H NMR (CDCl3): d 8.809 (d, J=6.0, 2H), 8.335(d, J=5.0, 2H), 8.090 (d, J=7.5, 2H), 7.750 (m, 6H), 6.543 (t, J=4.5,1H), 3.868 (t, J=5.0, 4H), 3.404 (t, J=5.0, 4H).

Scheme 2

4,5-dihydro-6-phenyl-4-(pyridin-4-yl)pyridazin-3(2H)-one

To a 200 ml, three-necked, round-bottomed flask equipped with a magneticstir bar, 150 ml pressure-equalizing addition funnel, reflux condenserand a glass stopper, was added 21 g (135 mmole) of 4-bromopyridine and70 of anhydrous THF. The system was oven-dried and flushed with argonbefore use. 135 ml (135 mmole) of THF solution of phenylmagnesiumbromide (1M) was placed in the pressure-equalizing addition funnel.Then, the grignard solution was added drop wise over a period of 10minutes. After the addition, the reaction was stirred for 15 minutes forcompletion. The solution of Grignard reagent was then obtained. Asolution of 4-pyridylmagnesium bromide obtained above was added to a hotsuspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in drytoluene (50 ml). The mixture was refluxed for 8 h, left overnight atambient temperature, then decomposed with a saturated solution ofammonium chloride. The organic layer was separated, and the aqueouslayer was extracted with 100 ml of ethyl acetate. The solvent wasremoved and the residue was crystallized from ethanol. The crystals werecollected by filtering and dried over a medium frit sintered glassfunnel in vacuo to give 5.6 g of white crystals. Yield was 50%,confirmed by ESI-MS. ESI-MS: m/z 252.1 (M+H+).

6-phenyl-4-(pyridin-4-yl)pyridazin-3(2H)-one

4.4 g (17.5 mmole) of 6-pyridazinone obtained above was placed in a 50ml single-necked round bottom flask followed by 4.7 g (35 mmole) ofanhydrous copper (II) chloride and then 20 ml of acetonitrile to give abrown yellow suspension. A reflux condenser was connected to the flaskand a dry tube filled with CaCl2 was fitted to the top of the condenser.The reaction mixture was heated to reflux in an oil bath (110 C) for 3h. The color of the reaction suspension changed to dark yellow once thereflux started. After the completion of the reaction (monitored byHPLC), the flask was removed from the oil bath and cooled to ambienttemperature. The mixture was poured on to 200 g of crushed ice andstirred vigorously for 10 minutes to give a gray precipitate and blueliquid. The precipitate was then collected by filtering (pH of thefiltrate was 1.5-2.0), and washed with 50 ml of a 1N HCl solution to ridthe solid of any remaining copper byproducts. This is followed bywashing with 100 ml of Milli-Q water to get rid of the acid in thesolid, and is monitored by checking the pH value of the filtrate. Thesolid was washed until the filtrate shows a pH of 7, after approximately5 washes. The solid was dried over a medium frit sintered glass funnelin vacuo to give 3.9 g of a blue gray solid. Yield was 90%, confirmed byESI-MS, ESI-MS: m/z 250.1 (M+H+).

3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine

2.0 g (8 mmole) of 6-phenylpyridazinone obtained above and 10 ml (54mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed ina 50 ml single-necked round bottom flask. The flask was connected with areflux condenser and a dry tube filled with CaCl2 was fitted to the topof the condenser. (HCl gas is formed in the reaction so a basic solutionsuch as NaOH may be needed to absorb HCl in a large-scale synthesis).The reaction mixture was stirred in an oil bath (90 C) for 2 h, thencooled to ambient temperature and poured onto crushed ice. (phosphorusoxychloride can be decomposed by water to give HCl and H3PO4). Themixture was then stirred vigorously for 10 minutes to give a whitesuspension. The suspension was neutralized with a 2N NaOH solution untilthe pH of the suspension was pH=7. The precipitate was filtered, washedthree times with 100 ml of water and dried over a medium frit sinteredglass funnel in vacuo to provide 1.8 g of a light pink powder. Yield was85%, confirmed by ESI-MS. ESI-MS: m/z 268.4 (M+H+).

4-pyridyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-6-189WH)

1.1 g (4.0 mmole) of 3-chloropyridazine obtained above was placed in a30 ml pressure vessel followed by addition of 2.6 g (16.0 mmole) of1-(2-pyrimidyl)piperazine and then 15 ml of 1-BuOH (reagent grade). Thevessel was sealed tightly and placed into an oil bath and stirred at130° C. (temperature of oil bath) for 3 days. The reaction mixture wasthen cooled to ambient temperature and transferred to a single-neckedflask for evaporation under reduced pressure. Removal of solvent gaverise to a brown-red residue that was treated with 30 ml of water to givea brown suspension. The solid was collected by filtering and washed with50 mL of water three times and dried over a filter funnel in vacuo toprovide 0.96 g of light yellow solid. Yield was 90%, confirmed by ESI-MSand NMR. ESI-MS: m/z 396.2 (M+H+). 1H NMR (CDCl3): d 8.809 (d, J=6.0,2H), 8.335 (d, J=5.0, 211), 8.090 (d, J=7.5, 2H), 7.750 (m, 6H), 6.543(t, J=4.5, 1H), 3.868 (t, J=5.0, 4H), 3.404 (t, J=5.0, 4H).

Example 14 Preparation of4,6-diphenyl-3-(4-phenylpiperazin-1-yl)pyridazine (MW01-7-029WH)

A synthetic reaction scheme for the preparation of4,6-diphenyl-3-(4-phenylpiperazin-1-yl)pyridazine (MW01-7-029WH) isdepicted in FIG. 20, and synthesis was carried out as described herein.The compound was prepared from 3-chloro-4,6-diphenylpyridazine (100 mg,0.37 mmol) in the same manner as described for MW01-7-057WH, yieldingwhite solid (123 mg, 0.31mmol, 83.1%). ESI-MS: m/z 393.2 (M+H+). NMR(CDCl3): d 8.107 (d, J=8.0. 2H), 7.736 (d, J=7.5, 2H), 7.651 (s, 1H),7.500 (m, 5H), 7.290 (t, J=8.5, J=6.5, 3H), 6.958 (d, J=7.5, 2H), 6.899(t, J=7.0, 1H), 3.487 (s, 4H), 3.214 (s, 4H).

Example 15 Preparation of4,6-diphenyl-3-(4-methylpiperazin-1-yl)pyridazine (MW01-7-027B-WH)

A synthetic reaction scheme for the preparation of4,6-diphenyl-3-(4-methylpiperazin-1-yl)pyridazine (MW01-7-027B-WH) isdepicted in FIG. 21, and synthesis was carried out as described herein.The compound was prepared from 3-chloro-4,6-diphenylpyridazine (100 mg,0.37 mmol) in the same manner as described for MW01-7-057WH, yieldingwhite solid (119 mg, 0.35 mmol, 94.5%). ESI-MS: m/z 331.1 (M30 H+). NMR(CDCl3): d 8.089 (d, J=7.5, 2H), 7.643 (d, J=7.5, 2H), 7.611 (s, 1H),7.510 (m, 6H), 3.365 (s, 3H), 2.472 (s, 4H), 2.337 (s, 4H).

Example 16 Preparation of4,6-diphenyl-3-(4-cyclohexylpiperazin-1-yl)pyridazine (MW01-3-065SRM)

A synthetic reaction scheme for the preparation of4,6-diphenyl-3-(4-cyclohexylpiperazin-1-yl)pyridazine (MW01-3-065SRM) isdepicted in FIG. 22, and synthesis was carried out as described herein.The compound was prepared from 3-chloro-4,6-diphenylpyridazine (300 mg,1.1 mmol) in the same manner as described for MW01-7-057WH, yieldingwhite solid (350 mg, 0.87 mmol, 87%). ESI-MS: m/z 399.2 (M+H+). 1H NMR(CDCl3): d 8.09 (d, J=7.5, 2H), 7.68 (d, J=7.5, 2H), 7.59 (s, 1H),7.56-7.42 (m, 6H), 3.39 (s, 4H), 2.62 (s, 4H), 2.273 (s, 1H), 2.01-1.78(m, 4H), 1.63 (d, J=12.5, 1H), 1.33-1.08 (m, 5H).

Example 17 Preparation of4,6-diphenyl-3-(4-isopropylpiperazin-1-yl)pyridazine (MW01-3-066SRM)

A synthetic reaction scheme for the preparation of4,6-diphenyl-3-(4-isopropylpiperazin-1-yl)pyridazine (MW01-3-066SRM) isdepicted in FIG. 23, and synthesis was carried out as described herein.The compound was prepared from 3-chloro-4,6-diphenylpyridazine (300 mg,1.1 mmol) in the same manner as described for MW01-7-057WH, yieldingwhite solid (290 mg, 0.81 mmol, 72%). m/z 359.2 (M+H+), 1H NMR (CDCl3):d 8.09 (d, J=7.5, 2H), 7.69 (d, J=7.5, 2H), 7.61 (s, 1H), 7.54-7.46 (m,6H), 3.40 (s, 4H), 2.72(m, 1H), 2.59 (s, 4H), 1.10 (d, J=6, 6H).

Example 18 Preparation of 4,6-diphenyl-3-piperazinylpyridazine(MW01-7-133WH)

A synthetic reaction scheme for the preparation of4,6-diphenyl-3-piperazinylpyridazine (MW01-7-133WH) is depicted in FIG.24, and synthesis was carried out as described herein. The compound wasprepared from 3-chloro-4,6-diphenylpyridazine (533 mg, 20 mmole) in thesame manner as described for MW01-7-057WH, yielding light yellow solid(550 mg, 17.4 mmole, yield 86.9%). ESI-MS: m/z 317.3 (M+H+). 1H NMR(CDCl3): d 8.086 (d, J=7.5, 2M), 7.705 (d, J=7.5, 2H), 7.619 (s, 1H),7.498 (m, 6H), 3.318 (d, J=4.0, 4H), 2.932 (d, J=4.0, 4H) 1.896 (s, 1H).

Example 19 Preparation of2-(4-(6-phenyl-4-(piperidin-1-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-7-107WH)

A synthetic reaction scheme for the preparation of2-(4-(6-phenyl-4-(piperidin-1-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-7-107WH) is depicted in FIG. 25, and synthesis was carried out asdescribed herein. The compound was prepared from MW01-6-127WH (200 mg,0.57 mmole) in the same manner as described for MW01-7-057WH, yieldinglight yellow solid (220 mg, 0.55 mmole, yield 96.3%). ESI-MS: m/z 402.5(M+H+).

Example 20 Preparation of6-methyl-4-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-7-057)

A synthetic reaction scheme for the preparation of6-methyl-4-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(MW01-7-057) is depicted in FIG. 26, and synthesis was carried out asdescribed herein. A mixture of 3-chloro-6-methyl-4-phenylpyridazine (100mg, 0.5 mmol), 1-(2-pyrimidyl)piperazine (400 mg, 2.0 mmol) in 3 ml of1-BuOH was heated with stirring at 130 C for 7 days. The solvent wasremoved by evaporation in vacuo, the residue was treated with water togive a suspension. The solid was then filtered off, washed with water,then 1:3, Ethyl Acetate:Petroleum ether, dried over filter tunnel invacuo to give light yellow solid (68 mg, 0.20 mmol, yield 41.7%).Purity >95%; ESI-MS: m/z 333.1 (M+H+). 1H NMR (CDCl3): d 8.310 (d,J=5.0, 2H), 7.678 (d, J=7.5, 2H), 7.476 (m, 3H), 7.119 (s, H), 6.509 (t,J=4.5, 1H), 3.785 (t, J=4.5, J=5.0, 4H), 3.277 (t, J=4.5, J=5.0, 4H),2.669 (s, 3H).

Example 21 Preparation of2-(4-(5-phenyl-6-(pyridin-4-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-2-163MAS)

A synthetic reaction scheme for the preparation of2-(4-(5-phenyl-6-(pyridin-4-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-2-163MAS) is depicted in FIG. 27, and synthesis was carried out asdescribed herein.

1,2-dihydro-4-phenylpyridazine-3,6-dione (MW01-2-077A-MAS)

4.0 g (23 mmole) of 3-phenylfuran-2,5-dione was added to a 100 mlsingle-necked round bottom flask followed by 2.9 g (27.6 mmole) ofhydrazine monohydrate and then 20 ml of reagent grade ethanol (95%). Theflask was fitted with a reflux condenser and the reaction mixture washeated to reflux in an oil bath at 110 degree (temperature of oil bath)and stirred for 2 h. The flask was then removed from the oil bath andthe reaction mixture cooled to ambient temperature. The stir bar wasremoved and the solvent was evaporated in vacuo in a water bath at 45degree. The residue was then treated with 50 ml of Milli-Q water andstirred for 10 minutes to give a suspension. The precipitate wascollected by filtering, washed with 100 ml of Milli-Q water, and driedover a medium frit sintered glass funnel in vacuo to give 3.9 g of whitesolid. Yield, 91%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H⁺).

3,6-dichloro-4-phenylpyridazine (MW01-2-082A-MAS)

1.5 g (8 mmole) of 6-phenylpyridazinone obtained above and 10 ml (54mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed ina 50 ml single-necked round bottom flask. The flask was connected with areflux condenser and a dry tube filled with CaCl2 was fitted to the topof the condenser. (HCl gas is formed in the reaction so a basic solutionsuch as NaOH may be needed to absorb HCl in a large-scale synthesis).The reaction mixture was stirred in an oil bath (90° C.) for 2 h, thencooled to ambient temperature and poured onto crushed ice. (phosphorusoxychloride can be decomposed by water to give HCl and H3PO4). Themixture was then stirred vigorously for 10 minutes to give a whitesuspension. The suspension was neutralized with a 2N NaOH solution untilthe pH of the suspension was pH=7. The precipitate was filtered, washedthree times with 100 ml of water and dried over a medium frit sinteredglass funnel in vacuo to provide 1.5 g of a white solid, Yield was 85%,confirmed by ESI-MS. ESI-MS: m/z 226.1 (M+H⁺).

2-(4-(6-chloro-5-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-2-114B-MAS)

A mixture of 3,6-dichloro-4-phenylpyridazine (1.35 g, 6 mmol),1-(2-pyrimidyl)piperazine (1.2 g, 6.6 mmol) in 10 ml of 1-BuOH washeated with stirring at 80° C. for 12 h. The solvent was removed byevaporation in vacuo, the residue was treated with water to give asuspension. The solid was then filtered off, washed with water, driedover filter funnel in vacuo to give white solid (1.8 g, 5.2 mmol, yield86.0%). ESI-MS: m/z 353.9.

2-(4-(5-phenyl-6-(pyridin-4-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine(MW01-2-163MAS)

Into a reaction tube were added MW01-2-114B-MAS (1.4 g, 4.0 mmol), K₂CO₃powder (1.7 g, 12.4 mmol), Pd(PPh3)4 (240 mg, 0.2 mmol),4-pyridineboronic acid (664 mg, 5.4 mmol) and 20 ml of DME. Argon wasthen flushed through the tube for 3 min. The tube was then sealedtightly and heated with stirring at 120° C. for 24 h. After cooled down,the mixture was filter through a celite earth, the filtrate was thenconcentrated and the residue was purified by column chromatographyeluting with 1:4, Ethyl Acetate:Petroleum ether. Light yellow needlecrystals were obtained (0.69 g, 1.74 mmol, yield 43.5%). Confirmed byESI-MS and NMR. ESI-MS: m/z 396.2 (M+H⁺).

Example 22 Preparation ofN-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-084WH)

A synthetic reaction scheme for the preparation ofN-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-084WH) is depicted in FIG. 28, and synthesis was carried out asdescribed herein.

4-chloro-6-phenylpyridazin-3(2H)-one (MW01-6-093WH) was synthesizedaccording to the procedure described by Coudert, P., et al. [18].

4-chloro-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (MW01-7-053WH)

A mixture of chloropyridazinone 1 (25.5 g, 0.12 mol),4-N,N-dimethylaminopyridine (0.20 g) and i-Pr2NEt (26.7 g, 0.21 mol) inanhydrous CH2Cl2 (300 mL) was stirred at 0 _(i)ãC (ice bath) for 30 min.Methoxymethyl chloride (25 g, 0.31 mol) was added and the mixture wasstirred at 0° C. for 1 h and then allowed to warm to r. t. The reactionwas stirred at r.t. till it complete. The solvent was then removed invacuo, the residue was treated with water, washed with dilute Na₂CO₃solution and extracted with EtOAc. The organic layer was dried overanhydrous Na₂SO₄, filtered and evaporated. The residue was then purifiedby recrystallization from 95% ethanol to give 20.1 light yellow solid.Yield 66.9%.

6-phenyl-4-(pyridin-4-yl)pyridazin-3(2H)-one (MW01-7-069WH)

The protected pyridazinone MW01-7-053WH (1.0 equiv.) was mixed witharylboronic acid (1.37 equiv.), Pd(PPh3)4 (0.05 equiv.) and K2CO3 (3.1equiv) and 200 mL of DME in a 350 ml of pressure vessel, flushed withargon for 3 min, and the mixture was then stirred and refluxed (oilbath, 120° C.) until the starting material had disappeared. Aftercooling, the solution was concentrated to dryness under reducedpressure, the residue was treated with water and filtered off. Thefiller cake was washed with water over filter funnel and then used fornext step directly. The residue obtained above was dissolved in 200 mlof EtOH, 6 N HCl (200 mL) was added and the reaction mixture wasrefluxed (oil bath, 120° C.) for 6 h, then it was allowed to cool toroom temperature, and concentrated to dryness under reduced pressure.The residue was neutralized with dilute NaOH solution. The suspensionwas then filter off, washed with water and dried over filter funnel.Recrystallization from 90% ethanol provided brown yellow solid. Yield80.4%. ESI-MS: m/z 294.3 (M+H⁺)

3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH)

This compound was prepared from MW01-7-069WH in the same manner asdescribed for MW01-6-127WH, yielding light yellow solid. ESI-MS: m/z268.4 (M+H⁺).

N-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4-yl)pyridazin-3-amine(MW01-7-084WH)

This compound was prepared from MW01-7-076WH in the same manner asdescribed for MW01-7-057WH, yielding gray solid. ESI-MS: m/z 330.4(M+H⁺).

The present invention is not to be limited in scope by the specificembodiments described herein, since such embodiments are intended, asbut single illustrations of one aspect of the invention and anyfunctionally equivalent embodiments are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description and accompanying drawings.Such modifications are intended to fall within the scope of the appendedclaims.

All publications, patents and patent applications referred to herein areincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. All publications, patents and patent applicationsmentioned herein are incorporated herein by reference tor the purpose ofdescribing and disclosing the methods etc. which are reported thereinwhich might be used in connection with the invention. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention.

TABLE 1 Compound Compound Synthetic Number Structure Code 1

MW01-ES1 4

MW01-ES112 10

MW01-ES159 11

MW01-ES21 12

MW01-ES31 13

MW01-ES60 14

MW01-ES61 16

MW01-ES75 17

MW01-ES81 18

MW01-ES91 20

MW01-1-04-L-D04 23

MW01-15-L-H07 24

MW01-1-16-L-F05 25

MW01-1-18-L-B09 31

MW01-1-035LKM 40

MW01-1-09-L-G07 41

MW01-2-03-L-C02 43

MW01-1-15-L-E09 44

MW01-1-16-L-B11 47

MW01-4-198B-Z 48

MW01-5-144A-Z 49

MW01-4-198C-Z 50

MW01-5-144C-Z 51

MW01-5-144D-Z 52

MW01-5-145A-Z 54

MW01-5-189Z 55

MW01-5-202B-Z 61

MW01-1-01-L-D06 65

MW01-1-01-L-E10 66

MW01-1-02-L-E08 70

MW01-1-03-L-D03 71

MW01-1-03-L-F03 73

MW01-1-03-L-G10 74

MW01-1-03-L-H06 75

MW01-1-04-L-C03 76

MW01-1-07-L-H04 88

MW01-1-100-L-A04 89

MW01-1-100-L-A05 90

MW01-1-100-L-A08 91

MW01-1-100-L-A09 92

MW01-1-11-L-E08 94

MW01-1-15-L-G09 97

MW01-1-16-L-G03 106

MW01-9-039Z 107

MW01-9-040Z 108

MW01-9-041Z 109

MW01-9-104A-Z 110

MW01-9-105A-Z 111

MW01-9-110A-Z 112

MW01-9-133A-Z 113

MW01-9-149A-Z 114

MW01-9-159A-Z 115

MW01-9-171Z 116

MW01-9-172Z 118

MW01-9-204Z 120

MW01-1-16-L-G08 122

MW01-17-L-G05 123

MW01-1-17-L-G11 125

MW01-1-17-L-H03 127

MW01-1-17-L-H11 130

MW01-1-18-L-A08 137

MW01-2-020SRM 143

MW01-2-056WH 149

MW01-1-18-L-A11 150

MW01-1-18-L-B03 151

MW01-1-18-L-B09 158

MW01-3-033WH 159

MW01-3-009WH 173

MW01-2-03-L-D02 175

MW01-2-06-L-F04 175A

????? 179

MW01-2-33-L-B02 180

MW01-3-01-L-G07 183

MW01-5-160WH 184

MW01-5-161WH 189

MW01-6-041WH 190

MW01-6-044WH 192

MW01-6-050WH 197

MW01-1-01-L-A10 198

MW01-1-01-L-B03 199

MW01-1-01-L-B09 201

MW01-1-01-L-E03 202

MW01-1-01-L-E04 205

MW01-1-18-L-B07 208

MW01-1-03-L-G03 210

MW01-1-04-L-C03 217

MW01-1-02-L-E03 218

MW01-1-02-L-E06 221

MW01-1-02-L-F02 223

MW01-1-02-L-F08 225

MW01-1-02-L-G05 226

MW01-1-02-L-G06 227

MW01-1-03-L-A02 229

MW01-1-03-L-B09 230

MW01-1-03-L-B10 231

MW01-1-03-L-C03 233

MW01-1-03-L-C08 235

MW01-1-03-L-E08 236

MW01-1-03-L-E09 240

MW01-1-04-L-A06 242

MW01-1-04-L-D10 250

MW01-1-05-L-B11 251

MW01-1-05-L-C02 254

MW01-1-05-L-G11 255

MW01-1-05-L-H05 266

MW01-1-08-L-D09 268

MW01-1-09-L-C06 270

MW01-1-09-L-G05 271

MW01-1-09-L-G07 272

MW01-1-09-L-G09 274

MW01-1-09-L-H07 275

MW01-1-15-L-A04 276

MW01-1-15-L-B02 278

MW01-1-15-L-B10 280

MW01-1-15-L-C04 282

MW01-1-15-L-D03 284

MW01-1-15-L-G10 292

MW01-1-17-L-A09 293

MW01-1-17-L-A11 294

MW01-1-17-L-B02 295

MW01-1-17-L-B10 296

MW01-1-17-L-E11 297

MW01-1-17-L-F03 298

MW01-1-17-L-H05 299

MW01-1-18-L-A09 308

MW01-2-03-L-B08 310

MW01-2-03-L-C05 313

MW01-2-03-L-G07 318

MW01-2-101-L-H08 319

MW01-2-10-L-E05 320

MW01-2-10-L-E06 321

MW01-2-20-L-B02 323

MW01-2-20-L-D05 324

MW01-2-20-L-E09 326

MW01-2-25-L-H06 328

MW01-3-01-L-G03 329

MW01-3-01-L-G04 331

MW01-3-01-L-G08 332

MW01-3-01-L-G09 335

MW01-3-06-L-E09 337

MW01-1-07-L-G07 339

MW01-1-15-L-C11 340

MW01-1-15-L-E09 341

MW01-1-16-L-B11 346

MW01-1-17-L-F10 347

MW01-1-17-L-F11 350

MW01-2-20-L-B11 352

MW01-3-01-L-F09 359

MW01-1-03-L-E05 360

MW01-1-03-L-A08 361

MW01-1-03-L-H08 362

MW01-1-01-L-H04 363

MW01-1-01-L-H06 366

MW01-1-03-L-E07 367

MW01-1-05-L-E05 368

MW01-1-03-L-B03 371

MW01-1-05-L-E07 372

MW01-1-03-L-A03 373

MW01-1-03-L-E03 374

MW01-1-01-L-H10 375

MW01-1-04-L-H08 376

MW01-1-01-L-G10 377

MW01-1-03-L-G11 380

MW01-1-04-L-B07 381

MW01-1-04-L-C09 382

MW01-1-10-L-G05

TABLE 2 Compound Compound Synthetic Number Structure Code 22

MW01-1-15-L-E08 26

MW01-2-02-L-H09 29

MW01-1-030A-LKM 30

MW01-1-030B-LKM 32

MW01-1-048AB- LKM 33

MW01-2-065LKM 34

MW01-2-127LKM 35

MW01-2-134LKM 36

MW01-2-146LKM 37

MW01-2-147LKM 38

MW01-1-02-L-B11 39

MW01-1-04-L-F10 42

MW01-2-33-L-A11 45

MW01-1-17-L-E06 46

MW01-1-045MAS 53

MW01-5-145B-Z 56

MW01-7-127AB-Z 60

MW01-1-01-L-B04 62

MW01-1-01-L-D10 63

MW01-1-01-L-E02 64

MW01-1-01-L-E08 67

MW01-1-02-L-H10 68

MW01-1-03-L-A05 69

MW01-1-03-L-B08 72

MW01-1-03-L-G09 87

MW01-1-08-L-E11 93

MW01-1-13-L-G06 95

MW01-1-16-L-D09 96

MW01-1-16-L-E02 105

MW01-9-038Z 121

MW01-1-17-L-G04 124

MW01-1-17-L-H02 126

MW01-1-17-L-H07 128

MW01-1-18-L-A02 129

MW01-1-18-L-A03 136

MW01-2-018SRM 138

MW01-2-023SRM 147

MW01-2-177A-WH 148

MW01-2-177B-WH 153

MW01-2-184WH 155

MW01-2-191A-WH 156

MW01-2-193B-WH 157

MW01-3-003WH 160

MW01-3-019A-WH 161

MW01-3-060A-WH 162

MW01-3-072WH 163

MW01-3-117WH 164

MW01-3-118WH 166

MW01-3-183WH 171

MW01-2-03-L-G03 172

MW01-2-03-L-C04 174

MW01-2-03-L-G03 176

MW01-2-102-L-C11 177

MW01-2-21-L-F04 178

MW01-2-24-L-G09 181A

186

MW01-5-188WH 188

MW01-6-003WH 191

MW01-6-046WH 200

MW01-1-01-L-C06 203

MW01-2-03-L-D09 204

MW01-1-01-L-B02 206

MW01-2-03-L-D09 207

MW01-2-03-L-G04 209

MW01-1-17-L-E05 211

MW01-1-04-L-C03 212

MW01-1-01-L-E11 213

MW01-1-01-L-F02 214

MW01-1-01-L-F03 215

MW01-1-01-L-G08 216

MW01-1-02-L-D11 219

MW01-1-02-L-E04 220

MW01-1-02-L-E11 222

MW01-1-02-L-F04 224

MW01-1-02-L-F09 228

MW01-1-03-L-A04 232

MW01-1-03-L-C04 234

MW01-1-03-L-E04 237

MW01-1-03-L-E10 238

MW01-1-03-L-G02 239

MW01-1-03-L-H04 241

MW01-1-04-L-D08 243

MW01-1-04-L-E03 244

MW01-1-04-L-E04 245

MW01-1-04-L-E09 246

MW01-1-04-L-F06 247

MW01-1-04-L-G06 248

MW01-1-04-L-H06 249

MW01-1-04-L-H07 252

MW01-1-05-L-F05 253

MW01-1-05-L-G10 256

MW01-1-05-L-H07 257

MW01-1-05-L-H09 258

MW01-1-05-L-H11 259

MW01-1-07-L-E07 260

MW01-1-07-L-G09 261

MW01-1-07-L-H03 262

MW01-1-07-L-H05 263

MW01-1-07-L-H06 264

MW01-1-08-L-C07 265

MW01-1-08-L-C09 267

MW01-1-08-L-E04 269

MW01-1-09-L-G04 273

MW01-1-09-L-G11 277

MW01-1-15-L-B07 279

MW01-1-15-L-B11 281

MW01-1-15-L-D02 282

MW01-1-15-L-D03 283

MW01-1-15-L-E10 285

MW01-1-15-L-H09 286

MW01-1-16-L-E05 287

MW01-1-01-L-F11 288

MW01-1-17-L-B05 290

MW01-1-16-L-E08 291

MW01-1-16-L-G07 297

MW01-1-17-L-F03 300

MW01-1-18-L-B04 301

MW01-1-18-L-B10 302

MW01-1-18-L-B11 303

MW01-1-18-L-C05 304

MW01-1-18-L-C06 305

MW01-1-18-L-C08 306

MW01-1-18-L-C10 307

MW01-1-18-L-D04 309

MW01-2-03-L-C03 311

MW01-2-03-L-D07 312

MW01-2-03-L-D08 314

MW01-2-03-L-G10 315

MW01-2-06-L-F06 316

MW01-2-09-L-B08 317

MW01-2-09-L-E10 322

MW01-2-20-L-B10 325

MW01-2-24-L-A05 327

MW01-3-01-L-G02 330

MW01-3-01-L-G05 333

MW01-3-06-L-B07 334

MW01-3-06-L-B08 336

MW01-1-07-L-G07 338

MW01-1-08-L-D03 342

MW01-1-16-L-E09 343

MW01-1-17-L-C09 344

MW01-1-17-L-E07 345

MW01-1-17-L-E08 348

MW01-1-18-L-A04 349

MW01-1-18-L-B05 351

MW01-2-33-L-A10 356

MW01-1-01-L-E06 357

MW01-1-01-L-H09 358

MW01-1-05-L-D07 365

MW01-1-03-L-D04 369

MW01-1-04-L-G02 379

MW01-2-24-L-E07

MW01-01-01-L-B07

MW01-7-084WH

MW01-7-085WH

MW01-7-091WH

MW01-10-12-L-G05

MW01-7-057WH

TABLE 3 Compounds of the Formula II2-(4-(6-phenylpyridazin-3-yl)piperazine-1-yl) pyrimidine and DerivativesCompound Compound Synthetic Number Structure Code

MWo1-2-5 069A-SRM 10

MW01-6-127WH

MW01-6-189WH

MW01-7-107WH

MW01-2-151SRM

MW01-2-069A-SRM 29

MW01-1-030A-LKM 33

MW01-2-065-LKM 34

MW01-2-127LKM 35

MW01-2-134LKM 36

MW01-2-146LKM 37

MW01-2-147LKM 46

MW01-1-045MAS 105

MW01-9-038Z 138

MW01-2-023SRM 147

MW01-2-177A-WH 155

MW01-2-191A-WH 252

MW01-1-05-L-F05 157

MW01-3-003WH 160

MW01-3-019A-WH 186

MW01-5-188WH 263

MW01-1-07-L-H06

TABLE 4 Concentration Dependent Activity in Cell Culture Compound FinalCode Assays

MW01-01-02-L-G05

MW01-01-03-L-E10

MW01-01-04-L-D08

MW01-01-18-L-A02

MW01-01-18-L-C02

MW01-02-03-L-G04

MW01-2-018SRM

MW01-2-023SRM

MW01-2-141SRM

MW01-2-163MAS

MW01-2-177A-WH

MW01-2-191A-WH

MW01-3-024SRM

MW01-3-027SRM

MW01-3-057SRM

MW01-3-065SRM

MW01-3-066SRM

MW01-3-183WH

MW01-4-179LKM

MW01-4-188LKM

MW01-7-027B-WH

MW01-7-029WH

MW01-7-031WH

MW01-7-100WH

MW01-7-102WH

MW01-7-133WH

MW01-9-039MZ

MW01-9-040MZ

MW01-2102LPI

MW01-2103LPI

TABLE 5

Structure 5

Structure 6

Structure 9

Structure 10

Structure 14

Structure 15

Structure 19

Structure 21

Structure 7

Structure 8

Structure 12

Structure 13

Structure 17

Structure 18

Structure 22

Structure 23

Structure 24

Structure 25

Structure 50

Structure 32

Structure 33

Structure 36

Structure 38

Structure 42

Structure 26

Structure 27

Structure 34

Structure 35

Structure 39

Structure 40

Structure 43

Structure 44

Structure 46

Structure 47

Structure 181

Structure 188

Structure 63

Structure 31

Structure 60

Structure 61

Structure 48

Structure 49

Structure 377

Structure 378

Structure 58

Structure 59

Structure 62

Structure 63

Structure 64

Structure 65

Structure 68

Structure 69

Structure 75

Structure 76

Structure 79

Structure 80

Structure 66

Structure 67

Structure 70

Structure 71

Structure 77

Structure 78

Structure 81

Structure 82

Structure 83

Structure 84

Structure 87

Structure 142

Structure 91

Structure 143

Structure 97

Structure 485

Structure 85

Structure 86

Structure 89

Structure 90

Structure 95

Structure 96

Structure 99

Structure 100

Structure 101

Structure 102

Structure 105

Structure 106

Structure 109

Structure 110

Structure 113

Structure 114

Structure 103

Structure 104

Structure 107

Structure 108

Structure 111

Structure 112

Structure 115

Structure 116

Structure 117

Structure 118

Structure 121

Structure 122

Structure 125

Structure 126

Structure 129

Structure 130

Structure 119

Structure 120

Structure 123

Structure 124

Structure 127

Structure 128

Structure 131

Structure 132

Structure 133

Structure 134

Structure 137

Structure 138

Structure 141

Structure 144

Structure 135

Structure 136

Structure 139

Structure 140

Structure 145

REFERENCES

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1-32. (canceled)
 33. A compound of Formula Ib:

wherein: R¹ is a substituted amino group; R² and R³ are independentlyhydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene,alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy,aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl,sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl,nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O,═S, carboxyl, carbonyl, carbamoyl, or carboxamide and R⁴, R⁵ and R⁶ areindependently hydrogen, alkyl, alkoxy, halo or nitro; or apharmaceutically acceptable salt thereof.
 34. A compound according toclaim 33, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 35. A compound accordingto claim 33, wherein the substituted amino group for R¹ has the formula—NR21R22, where R21 and R22 are any combination of hydrogen, hydroxyl,alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, carbonyl, carboxyl,amino, silyl, heteroaryl or heterocyclic, each of which are optionallysubstituted, provided that R21 and R22 are not both hydrogen.
 36. Acompound according to claim 33, wherein the substituted amino group forR¹ is methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino,isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino,cyclohexylamino, piperidinyl, hydrazinyl, diphenylmethylamino,tritylamino, trimethylsilylamino or dimethyl-tert.-butylsilylamino, eachof which are optionally substituted.
 37. A compound according to claim33, wherein R² is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl or tetrezolyl.
 38. A compound according to claim33, wherein R² is pyridinyl.
 39. A method for reducing neuroinflammationto treat a disease or condition which presents neuroinflammation in asubject, comprising administering to the subject a compound of claim 33.40. A method for reducing neuroinflammation to treat a disease orcondition which presents neuroinflammation in a subject, comprisingadministering to the subject a compound of claim
 34. 41. The method ofclaim 39, wherein progression of said disease or condition isameliorated or progresses to a less severe stage.
 42. The method ofclaim 39, wherein said compound reduces neuroinflammation associatedwith any one of traumatic brain injury, intracerebral hemorrhage, orAlzheimer's disease.
 43. The method of claim 39, wherein said compounddecreases neuroinflammation by acting on one or more of cell signalingmolecule production, activation of glia or glial activation pathways andresponses, proinflammatory cytokines or chemokines, oxidativestress-related responses, acute phase proteins, components of thecomplement cascade, protein kinase activity, cell damage and cell deathsignal transduction pathways.
 44. The method of claim 39, wherein saiddisease includes mild cognitive impairment (MCI).
 45. The method ofclaim 39, further comprising: administering a pharmaceuticallyacceptable carrier, excipient, or vehicle to said subject and whereinkinase activity, glial activation, neuronal cell damage, and/or neuronalcell death is reduced or inhibited.
 46. The method of claim 39, whereinthe progression of said disease is delayed.
 47. The method of claim 39,wherein the disease or condition treated is Alzheimer's disease,intracerebral hemorrhage or traumatic brain injury, which disease orcondition presents neuroinflammation.
 48. The method of claim 39,wherein the compound inhibits pro-inflammatory cytokines or chemokines.49. The method of claim 39, wherein the compound inhibits IL-1β, TNF-αand/or S100β.